Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3527-3561
REVIEW ARTICLE
Endothelial Cells in Physiology and in the Pathophysiology of
Vascular Disorders
By
Douglas B. Cines,
Eleanor S. Pollak,
Clayton A. Buck,
Joseph Loscalzo,
Guy A. Zimmerman,
Rodger P. McEver,
Jordan S. Pober,
Timothy M. Wick,
Barbara A. Konkle,
Bradford S. Schwartz,
Elliot S. Barnathan,
Keith R. McCrae,
Bruce A. Hug,
Ann-Marie Schmidt, and
David M. Stern
From the Department of Pathology and Laboratory Medicine and
Department of Medicine, University of Pennsylvania, Philadelphia, PA;
the Wistar Institute, Philadelphia, PA; the Department of Medicine,
Boston University School of Medicine, Boston, MA; the Nora Eccles
Harrison Cardiovascular Research and Training Institute, University of
Utah, Salt Lake City, UT; the Department of Medicine,
University of Oklahoma Health Sciences Center, Oklahoma City, OK; the
Boyer Center for Molecular Medicine, Yale University School of
Medicine, New Haven, CT; the School of Chemical Engineering, Georgia
Institute of Technology, Atlanta, GA; the Cardeza Foundation, Jefferson
Medical College of Thomas Jefferson University School of Medicine,
Philadelphia, PA; the Department of Medicine, University of Wisconsin
School of Medicine, Madison, WI; the Sol Sherry Thrombosis Research
Center, Temple University School of Medicine, Philadelphia, PA; and the
Departments of Physiology and Cell Biophysics, Columbia University
College of Physicians and Scientists, New York, NY.
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PART I |
THE ENDOTHELIUM has long been viewed as
an inert cellophane-like membrane that lines the circulatory system
with its primary essential function being the maintenance of vessel
wall permeability. Shortly after the first description of circulating
blood by William Harvey in 1628, the existence of a network of vessels
arose from studies of Malphigi, who described the physical separation
between blood and tissue.1 In the 1800s, von Reckingausen
established that vessels were not merely tunnels bored through tissues
but were lined by cells. The strength of Starling's experiments and his law of capillary exchange proposed in 1896 served to solidify the
belief that the endothelium was principally a selective but static
physical barrier, not withstanding Heidenhahn's description in 1891 of
the endothelium as an active secretory cell system. However, electron
microscopic studies of the vessel wall by Palade in 1953 and
physiological studies by Gowan in 1959 describing the interaction
between lymphocytes and endothelium of postcapillary venules stimulated
numerous subsequent studies that led to the current view of the
endothelium as a dynamic, heterogeneous, disseminated organ that
possesses vital secretory, synthetic, metabolic, and immunologic
functions.1
The endothelial cell (EC) surface in an adult human is composed of
approximately 1 to 6 × 1013 cells, weighs
approximately 1 kg, and covers a surface area of approximately 1 to 7 m2.2 ECs line vessels in every organ system and
regulate the flow of nutrient substances, diverse biologically active
molecules, and the blood cells themselves. This gate-keeping role of
endothelium is effected through the presence of membrane-bound
receptors for numerous molecules including proteins (eg, growth
factors, coagulant, and anticoagulant proteins), lipid transporting
particle (eg, low-density lipoprotein [LDL]),
metabolites (eg, nitrous oxide and serotonin), and hormones (eg,
endothelin-1), as well as through specific junctional proteins and
receptors that govern cell-cell and cell-matrix interactions.
The endothelium also plays a pivotal role in regulating blood flow. In
part, this results from the capacity of quiescent ECs to generate an
active antithrombotic surface that facilitates transit of plasma and
cellular constituents throughout the vasculature. Perturbations, such
as those that may occur at sites of inflammation or high hydrodynamic
shear stress, disrupt these activities and induce ECs to create a
prothrombotic and antifibrinolytic microenvironment. Blood flow is also
regulated, in part, through secretion and uptake of vasoactive
substances by the endothelium that act in a paracrine manner to
constrict and dilate specific vascular beds in response to stimuli such
as endotoxin.
Detailed study of endothelial function first became feasible with the
development in the 1970s of techniques to culture ECs in
vitro.3-5 Limitations of this approach have become apparent recently with the realization that cell culture perturbs ECs from their
quiescent in vivo state (0.1% replications per day) to an activated
phenotype (1% to 10% replications per day) with loss of specialized
functions associated with diverse vessels and organ systems. More
complex analytic systems now exist that incorporate changes in EC
properties imparted by plasma and cellular blood elements, by rheologic
factors, and by cell-cell interactions that occur within the vessel
wall. Genetic recombination studies in mice are likely to advance
understanding of ECs in both their physiologic and pathologic roles in
thrombosis, atherosclerosis, tumor metastasis, and organ rejection.
The purpose of this review is to provide a broad overview of EC
participation in several biological processes judged to be relevant to
clinical hematologists and investigators of vascular biology. Part I
will principally examine the known physiologic roles of the
endothelium, whereas Part II will discuss the interactions between ECs
and blood cells and emphasize the contribution of the EC to the
pathogenesis of specific diseases. Because of the introductory nature
of this review, many topics and important contributions have been
omitted, including the involvement of ECs in hematopoiesis,
neuroendocrinology, cell aging, cellular integrins and matrix
interactions, vascular permeability, lipid metabolism, the lymphatic
vasculature, and the endothelium as a target for gene therapy. We hope
that the abbreviated bibliographies will serve as an introduction to
readers who wish to further investigate EC biology.
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VASCULOGENESIS AND ANGIOGENESIS |
Overview of early vascular development.
Recently developed techniques that permit alteration of genomic
sequences and manipulation of developing embryonic tissues have
provided important insights into molecular and genetic elements that
regulate vascular development.6 These studies show that the
cardiovasculature is the first system to form in the gastrulating embryo. The de novo organization of ECs into vessels in the absence of
any pre-existing vascular system is referred to as vasculogenesis and
only occurs in the early embryo. Angiogenesis, the continued expansion
of the vascular tree as a result of ECs sprouting from existing
vessels, occurs in avascular regions of the embryo and is repeated many
times in the mature animal, most commonly during wound healing and
tumor metastasis7 (Fig 1). It
remains uncertain how the pattern of the vascular tree is established
or which factors govern the site of sprouting or the route taken by
migrating ECs during angiogenic expansion.
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| Fig 1.
The formation of new vessels during vasculogenesis and
angiogenesis. Vasculogenesis, the de novo organization of ECs into vessels in the absence of preexisting vascular structures, takes place
during embryogenesis in the blood islands of the yolk sac (pictured)
and in the embryo through expression of growth factors, in particular
fibroblast growth factor (FGF) and vascular endothelial growth factor
(VEGF). The tyrosine receptor kinases, VEGFR-1 (flk-1) and VEGFR-2
(flt-1), are expressed on mesenchymal cells and newly formed ECs,
respectively, and are essential for the generation and proliferation of
new ECs and the formation of tubal EC structures. Angiogenesis, the
continued expansion of the vascular tree, is mediated through the
expression of additional tyrosine kinase receptors, tie-2 (tek), which
binds to Ang1 and Ang2 (angiopoietins), resulting in the maintenance of
mature vessels, the development of new vessels, and the regression of
formed vessels in processes dependent on a combination of factors, most
notably the presence or absence of growth factors.
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Origin of the vascular endothelium.
Molecular events involved in EC differentiation from the early mesoderm
remain uncertain. Vascular and hematopoietic tissues develop together,
beginning shortly after implantation with the formation of blood
islands within the primitive yolk sac8 (Fig 1) composed of
two cell types: (1) angioblasts that form the outer layer of ECs
encasing the blood island; and (2) hematopoietic stem cells, in the
inner cluster, from which the first embryonic blood cells develop.
Angioblasts committed to EC differentiation are found primarily in
embryonic mesoderm,9 whereas the early epiblast also
contains a subpopulation of hematopoietic stem cells.10 Recently, angioblasts have been identified in the adult as
well.11 The endoderm is the initial stimulus for angioblast
formation.8,9 Within the embryo proper, the first
angioblasts arise from the lateral mesodermal plate and cardiac
crescent8,9; some cells migrate into the forming brain,
whereas others assemble into the endocardium of the early heart tube.
Other angioblasts form a plexus of ECs at the base of the primitive
heart tube that assemble into the vitelline vessels, allowing blood
cells from the yolk sac to circulate within the body of the
embryo.8 The vasculature of the viscera is formed from ECs
that differentiate directly from the surrounding mesenchyme
incorporated into the angiogenic extensions of invading
vessels.12 For example, as the airway of the developing
lung expands, endodermally derived cells of the branching airway
provide directional queues for advancing branchial arteries and induce
formation of angioblasts that become part of the pulmonary
vasculature.13 Vasculogenic activity of early organ
rudiments was shown through engraftment experiments using pieces of
early quail lung and chick embryos. These experiments lead to the
hypothesis that endoderm, but not ectoderm, induces vasculogenesis but
that both endoderm and ectoderm can support angiogenesis14;
recent experiments suggest additional sources of endothelial growth
factors may exist.15
Genetic programs regulating EC differentiation and early vascular
development.
The best insight into molecular events required to initiate and
maintain vascular development has come from detailed analyses of mouse
embryos in which the genes for specific polypeptide growth factors or
their transmembrane receptor tyrosine kinases (RTKs) have been
inactivated. Such experiments show that initiation of vascular
development requires both basic fibroblast growth factor (
FGF) and
vascular EC growth factors (VEGF; see Beck and D'Amore16 for a detailed discussion of growth factors and vascular development). Three alternatively spliced isoforms of VEGFs, members of the platelet-derived growth factor family (VEGF, VEGF-B, and
VEGF-C17), interact with specific tyrosine kinase
receptors. The growth factor-receptor interactions include VEGFR-1
(also known as flt-1 or fms-like tyrosine kinase-1) with VEGF and a
related placenta growth factor (PlGF); VEGFR-2 (known alternatively as
flk-1, fetal liver kinase-1; or Kdr, kinase-inserted domain containing
receptor) with both VEGF and VEGF-C; and VEGFR-3 (originally designated
flk-4) with VEGF-C. All VEGFs stimulate receptor autophosphorylation
and EC replication and migration. The crucial role of this ligand in early vasculogenesis is demonstrated by the fact that loss of the VEGF
gene results in embryonic death. Subsequent assembly of ECs into
vessels requires activation of VEGFR-1 on the surface of the newly
differentiated cells.18,19 The decision for a vessel to
become a vein or an artery appears to be under the control of yet
another growth factor, VEGFR-3,20 that is expressed later in development only on ECs that will become veins or lymphatic vessels.
Expansion of the vascular tree, continued endocardial and ventricular
development, and formation of the vascular wall is controlled by two
members of a second family of RTKs and their ligands,19 tie-1 (tyrosine kinase with Ig and epidermal growth factor homology domains) and tie-2 or tek (tunica interna EC kinase). Two ligands, termed angiopoietin-1 and angiopoietin-2,21,22 are specific for tie-2 and are synthesized by cells surrounding the developing vessels. Ligand binding results in autophosphorylation of tyrosine residues in the intracellular domain of tie-2, but does not lead to EC
replication or tube formation, as is the case for other endothelium-associated receptor-ligand interactions. Interestingly, angiopoietin-2 appears to function as an antagonist for angiopoietin-1, blocking its binding to tie-2. Targeted mutations of the genes for
either tie-2 or angiopoietin-1 result in embryos with abnormal hearts
and vessels with poorly formed walls.23 This has led to the
suggestion that angiopoietin-1 acts via its receptor on ECs to
stimulate the production of growth factors that, in turn, stimulate the
differentiation of surrounding mesenchyme into pericytes or smooth
muscle cells required for vessel wall formation.24 This is
consistent with the phenotype of a Tie-2 mutation in humans that leads
to smooth muscle deficiencies around small vessels and
microaneurysms.25 These observations suggest that carefully regulated activity of tie-1 and 2 is required for continued vascular branching and vessel remodeling. Thus, the assembly of the early vascular tree depends on the programmed expression of at least two sets
of RTKs and their ligands, one set for EC differentiation and
initiation of vessel formation and the other for subsequent branching,
establishment of capillary beds, and vessel wall formation.
Although genetic manipulations now possible in the mouse have provided
important insights, there is much that we do not know about vascular
development. Random genetic mutations introduced into the zebrafish
have also generated many surprising and fascinating cardiovascular
anomalies.6,26 For example, zebrafish can be induced to
develop with hearts that do not contain an endocardium although the
remainder of the vascular system appears functional. Thus, it is likely
that a combination of genetics and developmental biology, unencumbered
by previous assumptions, will continue to show new genes and suggest
new paradigms that will advance our understanding of vascular
development.
Extracellular matrix and matrix adhesion receptors in vascular
development.
The ability of ECs to form capillary-like tubes is regulated not only
by specific cytokine/receptor combinations, but also by the
extracellular matrix. For example, human umbilical vein ECs (HUVECs)
exposed to transforming growth factor- (TGF-) grow as a rapidly dividing monolayer if cultured on a flat surface coated
with type I collagen.27 However, under similar TGF- exposure, but within a type I collagen gel, ECs spontaneously organize
into capillary-like tubules and continue to divide. Several kinds of
molecules on the EC surface act together to mediate cell-extracellular matrix (ECM) interactions, including proteoglycans as well as proteins.
The best studied family of receptors that mediate cell-matrix interactions is the integrins,28 which serve both a
tethering and an information transfer function. Integrin-ligand binding triggers cytoskeletal organization at specific sites on the surface membrane to facilitate cell movement or maintain tissue stability. Binding also activates intercellular pathways that can result in either
cell replication or programmed cell death.29
Cells express more than one integrin and the combination of integrins
expressed during embryonic development is constantly changing,
suggesting that specific combinations are required as development
proceeds. Experimental results in the developing mouse embryo suggest
that functional compensation by integrins can occur during
embryogenesis. It is also possible that receptors required for
angiogenesis in early development may differ from those required for
collateral vessel formation or tumor angiogenesis or that both gene
inactivation and the introduction of inhibitory agents have unknown
secondary effects. Similarly, mouse embryos continue to develop
normally when genes for certain ECM components have been inactivated,
whereas inactivation of other genes, such as the abundant fibronectin,
results in early embryonic lethality.30 Similarly, knocking
out the gene for a fibronectin receptor subunit (
51) also results in a poorly developed
heart and vascular system and early embryonic death.30
Again, other integrins, most likely v3,
appear to compensate for the absence of
51 during preimplantation development and
early gastrulation, but are unable to do so as development proceeds.
Endothelial cell-cell interactions and vessel formation.
Angioblasts and ECs must contact like cells for vessels to sprout and
lengthen. Such cell-cell adhesion is mediated by a distinct series of
cell surface receptors that includes platelet EC adhesion molecule
(PECAM-1),31 a member of the Ig superfamily, and vascular endothelial (VE)-cadherin.8 ECs express two isoforms of
PECAM that mediate cell adhesion that differ in their requirement for divalent cations and sulfated proteoglycans. VE-cadherin, also known as
cadherin-5, found almost exclusively on ECs, promotes cell-cell
adhesion by a calcium-dependent homotypic mechanism,32 ie,
in the presence of calcium, VE cadherin from one cell binds to the
VE-cadherin expressed on an adjacent cell. As the vessel matures, more
classic junctional complexes, such as tight junctions and gap
junctions, form depending on the function of the particular vascular
bed. Thus, during vascular development, junction formation initially
involves rather weak adhesion complexes, likely required for cell-cell
recognition, that facilitate the assembly of additional junctional
complexes. However, the factors that determine the organ-specific
nature of junction formation remain unknown.
Proteinases and vascular development.
Vascular development may be regulated by some of the same factors that
are involved in the control of blood clotting and capillary formation.
EC movement through the ECM is tightly regulated and requires integrin
mediated cell-matrix adhesion complex formation and subsequent
disassembly. This involves repetitive cycles of reversible
integrin/matrix binding, assembly, and disassembly of cytoskeletal
elements as well as matrix degradation restricted to the advancing edge
of the moving cell.33 This is accomplished through the
organization of active molecular complexes that approximate integrins
and integrin ligands with matrix metalloproteinases and plasminogen
activators with their respective substrates and inhibitors at sites of
cell-matrix interaction.34 It has long been hypothesized
that, when ECs are exposed to angiogenic stimuli, plasminogen
activation is initiated through the binding of plasminogen and
urokinase to their receptors. This leads to the formation of plasmin
that activates prometalloproteases, degrades noncollagenous components
of the matrix, provides a path for cell migration, and releases
peptides that can promote or inhibit continued
angiogenesis.35 Two peptides, angiostatin and
endostatin,36,37 are currently being evaluated for clinical
use in reversing tumor angiogenesis.36 However, much of the
dogma regarding the role of plasmin in angiogenesis may have to be
revisited in light of recent data indicating that transgenic animals
with targeted disruption in the genes for tissue-type plasminogen
activator (t-PA), urokinase (u-PA), the urokinase receptor (u-PAR), and
plasminogen appear to develop a normal vasculature in the absence of
trauma or other stressors (see below).
Perspective.
The induction of embryonic angioblasts to differentiate into ECs,
organize into a vascular network, and subsequently populate the
specialized vascular bed of an organ results from a complex genetic
program, the details of which are only now emerging. This program is
not only sensitive to the composition and structure of the ECM but is
influenced by cell-cell contact as well as angiogenic and angiostatic
growth factors and peptides generated by vascular expansion itself.
Many of these same events are recapitulated after injury or as part of
an inflammatory response and, if allowed to proceed unchecked (eg,
tumor angiogenesis and diabetic retinopathy), can have serious
consequences for the organism. Insight into the molecular and genetic
programs involved in vascular differentiation may suggest better
approaches to minimize ischemic tissue damage, avoid tissue rejection,
stimulate wound healing, and inhibit tumor growth. This section has
focused on the development of the vascular endothelium; however, the
formation of the basement membrane, the induction and differentiation
of vascular smooth muscle cells, and the complex process of assembling
the elastic lamina are all essential to vessel formation and are under
separate regulation. Ultimately, prevention of devastating effects from
congenital abnormalities and facilitation of normal vascular function
will, in a large part, be influenced by our ability to manipulate
molecular mechanisms involved in vascular development.
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EC HETEROGENEITY |
Many human vascular diseases are exquisitely restricted to specific
types of vessels. For example, the contribution of platelets to the
pathogenesis of arterial and venous thrombosis differs as does the
susceptibility of these two types of vessels to atherosclerosis. It is
also common for vasculitis to show marked predilection for specific
arteries, veins, or capillaries or for certain organs. Tumor cells may
show similar predilection to metastasize through particular vascular
beds.38 Even when systemic risk factors are clearly
evident, such as is the case with inherited disorders of lipoprotein
metabolism or proteins that control coagulation, there is marked
regional variation in disease expression. Furthermore, clinical events
such as thromboses are generally episodic and often localized to single
vessels. The basis for variation is poorly understood, but may lie, in
part, in the heterogeneity of ECs themselves (see Augustin et
al2 and McCarthy et al39 for reviews).
To date, appreciation of EC function has been largely based on the
behavior of cultured umbilical vein ECs (HUVECs). Indeed, it is
remarkable that so many concepts in vascular biology have been
predicated on the repertoire of umbilical ECs studied under such
potentially unphysiologic in vitro conditions; this is especially true
considering their derivation from a type of vessel that rarely, if
ever, is affected by the most common human vascular disorders. More
recently, there has been greater appreciation that EC heterogeneity may
contribute both to the maintenance of adaptive processes and to the
development of disorders restricted to specific vascular beds.
EC heterogeneity among and within tissues.
Variation in the appearance of capillary endothelium from different
vascular sites has long been recognized and appears well suited to
postulated differences in function (Fig 2).
For example, the brain and retina are lined by continuous ECs connected
by tight junctions that help to maintain the blood-brain barrier; the
liver, spleen, and bone marrow sinusoids are lined by discontinuous ECs
that allow cellular trafficking between intercellular gaps; while the
intestinal villi, endocrine glands, and kidneys are lined by
fenestrated ECs that facilitate selective permeability required for
efficient absorption, secretion, and filtering (see Dejana32 for review). ECs from diverse tissues are also
heterogeneous with respect to their surface phenotype and protein
expression. For example, von Willebrand factor (vWF), used commonly as
a marker for ECs, is not expressed uniformly on cells from all types of vessels,40,41 the expression of tissue type plasminogen
activator is limited in vivo to approximately 3% of vascular
ECs,42 and the constitutive expression of u-PA is
reportedly confined to renal ECs,43,44 which are also
uniquely susceptible to injury by verotoxin.45
Microvascular ECs also differ in their susceptibility to undergo
apoptosis induced by plasma from patients with thrombotic thrombocytopenic purpura.46 The induction of tissue factor
after infusion of cytokines or endotoxin is similarly restricted to specific vessels,47 among many other examples of
heterogeneity at the level of protein expression.
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| Fig 2.
EC heterogeneity. (A) Electron micrograph showing the
junction between two capillary ECs in a guinea pig pancreas
(micrographs reprinted with permission from R.F. Bolender, The
Journal of Cell Biology, 1974, vol. 61, p. 269). (B) Electron
micrograph demonstrating the diversity of ECs from two types of
capillaries: (1) vesicular invaginations (arrow) on both luminal and
abluminal plasma membrane of a muscle capillary EC; (2) fenestrated
capillary from the lamina propria of the colon with thin diaphragms
(arrow) covering the plasma membrane pores (micrographs reprinted with
permission from E. Weihe, Textbook of Histology, (ed 12),
1994, p. 391, courtesy of Chapman and Hall).
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One of the clearest examples of EC heterogeneity lies in the expression
of homing receptors involved in cell trafficking. In the mouse,
Lu-ECAM-1 (lung-specific EC adhesion molecule) is exclusively expressed
by pulmonary postcapillary ECs and some splenic venules,48
whereas Mad-CAM-1 (mucosal addressin cell adhesion molecule-1) is
expressed primarily on high endothelial venules in Peyer's patches of
the small intestine.49 Microvascular ECs derived from the
bone marrow show an affinity for binding megakaryocytes and
CD34+ progenitor cells and constitutively secrete
hematopoietic stimulating factors such as Kit-ligand, granulocyte
colony-stimulating factor, granulocyte-macrophage colony-stimulating
factor, and interleukin-6 (IL-6), which help control trafficking,
proliferation, and hematopoietic lineage-specific
differentiation.50 Tumor cells may show clear preferential
adhesion to the endothelium of specific organs paralleling their in
vivo metastatic propensities (see McCarthy et al39 for
review).
Microvascular ECs cultured from the brain, liver, and other organs each
express distinct patterns of cell surface markers, protein
transporters, and intracellular enzymes.51 These
tissue-specific phenotypic differences can be maintained for some time
under identical tissue culture conditions (eg, Grau et
al52). Distinct subsets of ECs often exist within a single
organ. In situ studies of adult human liver show two distinct
sinusoidal EC phenotypes: hepatic periportal vessels express PECAM-1
and CD34, whereas sinusoidal intrahepatic ECs do not.53
During the development of the human liver, ECs progress from a
phenotype closely resembling adult hematopoietic sinusoidal bone marrow
ECs, which supports fetal intrahepatic hematapoiesis, to one resembling
adult hepatic sinusoidal ECs, including the expression of the
T-lymphocyte marker CD4.54
Environmental and genetic regulation of EC phenotype.
There is extensive evidence to indicate that heterogeneity develops in
part as a result of variation in exposure of EC to environmental
stimuli, some of which act only over short distances or even require
cell-cell contact to effect change. Numerous exogenous factors affect
EC phenotype, including mechanical forces, soluble growth promoters and
inhibitors, cytokines, plasma lipids and proteins [eg, thrombin,
plasmin, antibodies, Lp(a), etc], and contact with circulating and
tissue-based cells (eg, smooth muscle cells and pericytes) and with the
ECM, microbes, and their soluble products.
There are numerous examples of how the microenvironment can regulate
the endothelial phenotype, a phenomenon that has been referred to as
transdifferentiation.2 For example, aortic ECs cultured on
extracellular matrix derived from the lung are induced to express
Lu-ECAM-1,48 whereas the cells develop fenestrae when
cultured on matrix derived from kidney-derived MDCK
cells.55 Transplantation studies in the chick-quail system
illustrate that ECs can take on the characteristics of the tissue into
which they are transplanted in vivo,56 whereas other
examples show that ECs acquire a different phenotype ex
vivo.57 Studies in transgenic mice expressing the Lac Z
reporter gene under control of 2,182 bp of the 5
flanking
sequence and the first exon and intron of the vWF gene suggest that
expression is regulated by signals derived from the local
microenvironment that influence pathways specific for particular
vascular beds.58
EC heterogeneity can thus arise as a consequence of local
concentrations of exogenous effectors or due to intrinsic variations in
responsiveness (reviewed in McCarthy et al39). ECs grown on
extracts of basement membrane from different organs have been observed
to develop preferential adhesivity for tumor cells prone to metastasize
to that organ.59 ECs derived from saphenous vein have been
reported to synthesize less prostaglandin I2
(PGI2) than those from the internal mammary
artery, a finding that may contribute to the rapidity with which
pathogenic changes may develop in venous bypass grafts placed under
arterial pressure.60 Possible genetic bases for EC
diversity have only recently been considered and have not been studied
in depth. Microvascular and macrovascular ECs differ in the
fastidiousness of their growth, propsensity to form capillary-like
structures, synthesis of PGI2, and expression of adhesion
receptors for lymphocytes, among other properties (see Ades et
al61 for review). Tissue-specific transcription factors or signal transduction molecules responsible for activating and/or de-repressing transcription apparati in a
tissue-specific manner are only beginning to be understood.
Identification of these control factors will be important in the design
of vectors that will enable expression of EC proteins in a
tissue-specific manner.
The effects of cell culture.
Only in the past few years has the technology become available that
permits in situ study of EC behavior. These studies indicate that the
constitutive phenotype of ECs is unstable and their behavior can change
rapidly once explanted. Commonly used culture conditions may activate
or otherwise alter the endothelial phenoytpe (eg, Grant et
al62). There is, as yet, no model for generating the resting EC in vitro. Thus, all the information described in subsequent sections should be considered in the context of the cell source as well
as the ex vivo culture conditions, including passaging, the
presence/omission of shear forces, and factors released into blood that
alter the behavior of the endothelium from that which occurs in healthy
blood vessels in vivo. Thus, much may be gained in the future by a more
critical consideration of EC heterogeneity both in terms of
understanding homeostasis and vascular pathology, as well as in
targeting the delivery of gene therapy, antithrombotic agents, and
antitumor agents to an anatomically or functionally distinct
endothelial region.63
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VASOREGULATION |
The endothelium not only provides a structural barrier between the
circulation and surrounding tissue, but ECs also secrete mediators that
influence vascular hemodynamics in the physiologic state
(Table 1). ECs contribute to the regulation
of blood pressure and blood flow by releasing vasodilators such as
nitric oxide (NO) and prostacyclin (PGI2), as well as
vasoconstrictors, including endothelin (ET) and platelet-activating
factor (PAF). These chemically diverse compounds are not stored in
intracellular granules. Rather, their major biologic effects are
regulated by localization of specific receptors on vascular cells,
through their rapid metabolism, or at the level of gene transcription.
NO is constitutively secreted by ECs, but its production is modulated
by a number of exogenous chemical and physical stimuli, whereas the
other known mediators (PGI2, ET, and PAF) are synthesized
primarily in response to changes in the external environment.
NO.
ECs elaborate NO, a heterodiatomic free radical product generated
through the oxidation of L-arginine to L-citrulline by NO synthases.64 One isoform, eNOS or the Nos3 gene product, is constitutively active in ECs but is stimulated further by
receptor-dependent agonists that increase intracellular calcium and
perturb plasma membrane phospholipid asymmetry.65
Receptor-dependent agonists that stimulate eNOS include thrombin,
adenosine 5'-diphosphate, bradykinin, substance P, and muscarinic
agonists, in addition to shear stress66 and cyclic
strain.67 The increase in eNOS activity evoked by shear
stress contributes to the phenomenon of flow-mediated vasodilatation,
an important autoregulatory mechanism by which blood flow increases in
response to exercise.68 This is in part a result of
shear-induced transcriptional activation due to the presence of a shear
response consensus sequence, GAGACC, in the promoter of the Nos3
gene.69 In addition to eNOS, cytokines have been shown to
stimulate bovine microvascular endothelium in culture to express an
inducible isoform of NO synthase, iNOS, or the Nos2 gene
product.70 EC-derived NO has several important effects on
the vasculature. First, NO maintains basal tone by relaxing vascular
smooth muscle cells71 through the binding of NO to the heme
prosthetic group of guanylyl cyclase. Endothelial-derived NO also
inhibits platelet adhesion, activation, secretion, and aggregation and
promotes platelet disaggregation, in part through a cyclic
GMP-dependent mechanism.72 PGI2, which does not
affect platelet adhesion,73 acts synergistically with NO to
inhibit other steps in the platelet activation cascade.74
NO also inhibits expression of P-selectin on platelets and, by
inhibiting the agonist-dependent increase in intraplatelet
calcium,72 suppresses the calcium-sensitive conformational
change in the heterodimeric integrin glycoprotein IIb3 (GP IIb-IIIa) required for
fibrinogen binding.75 Additionally, NO appears to promote
platelet disaggregation indirectly by impairing the activity of
phosphoinositide 3-kinase, which normally supports conformational
changes in IIbIIIa, rendering its
association with fibrinogen effectively irreversible.76
In addition to these effects on the vasculature, endothelial-derived NO
inhibits leukocyte adhesion to the endothelium77,78 and
inhibits smooth muscle cell migration79 and
proliferation.80 These latter effects serve to limit
neointimal proliferation that occurs after vascular injury and,
combined with its stimulatory effect on EC migration and
proliferation,81 suggest that NO helps to sustain vascular
reparative mechanisms.
ECs also produce a less well-characterized compound known as
endothelium-derived hyperpolarizing factor (EDHF) that promotes vascular smooth muscle relaxation (see Garland et al82 for
review). Muscarinic agonists stimulate ECs to release EDHF, causing a
transient hyperpolarization of the cell membrane. It has been proposed
that EDHF exerts its vascular effects by activating ATP-sensitive
potassium channels, smooth muscle sodium-potassium ATPase, or
both,83 but its role in vascular (patho)physiology requires
further study.
ET.
Remarkably, ECs produce not only the potent vasodilator NO, but also
synthesize endothelin-1 (ET),84 the most potent
vasoconstrictor identified to date. Endothelins comprise a family of
21-amino acid peptides produced by many cell types.84 ET-1
is not stored in granules85 but is formed after
transcription of the gene encoding preproendothelin-1, the inactive
precursor of ET-1, after stimulation by hypoxia, shear stress, and
ischemia. ET-1 released from ECs binds to the abundant
G-protein-coupled ET-A receptor expressed on vascular smooth muscle
cells, which results in an increased intracellular calcium
concentration and, in turn, increases vascular smooth muscle cell
tone.86 Of interest, this effect of ET-1 persists after the
hormone dissociates from its receptor through longer-lived effects on
intracellular calcium. NO shortens the duration of these effects by
accelerating the restoration of intracellular calcium to basal
levels.87 The interplay between ET-1 and ET-A receptors
likely contributes to basal vascular tone as well. ET-1 potentiates the
vasoconstrictor actions of catecholamines, which, in turn, potentiate
the actions of ET-1. In states of endothelial dysfunction, such as
atherosclerosis, in which concentrations of bioactive NO are reduced,
the relatively unopposed actions of ET-1 promote vasoconstriction and
smooth muscle proliferation.88
Prostacyclin (PGI2) and PAF.
The contribution of ECs to the regulation of vasomotor tone is even
more finely regulated as evidenced by the production of additional
vasoactive compounds such as prostacyclin (PGI2) and PAF.
Prostacyclin and PAF factor provide an interesting contrast. Both are
intercellular signaling molecules synthesized by stimulated ECs in
vitro and in vivo.89 Both are lipids: PGI2
being an eicosanoid and PAF being a
phospholipid.90,91 Neither is constitutively present in resting human ECs nor stored within the cell. The synthesis of each is induced rapidly by humoral and mechanical stimuli via discrete, regulated pathways.90,91 Once formed,
PGI2 and PAF have relatively short half lives, one of
several features that limits the magnitude of their signals and exerts
control over their biologic activities.92,93
However, a major difference between the two factors lies in the range
over which they exert their effects: PAF acts in a juxtacrine fashion,
whereas PGI2 acts as a paracrine signaling molecule. PAF,
expressed on the surface of the endothelium, remains cell-associated even in the presence of physiologic concentrations of albumin or other
acceptor molecules91 and binds to and activates its receptor on leukocytes,94 fulfilling critical criteria of a juxtacrine signaling molecule. Consistent with this notion, PAF synthesized by cultured human ECs acts in concert with P-selectin (see
below) to promote leukocyte adhesion.94
In contrast, PGI2 is rapidly released from
ECs,95 although the export mechanism has not been precisely
defined. Thus, PAF and PGI2 have spatially differentiated
realms of signaling, even though both derive from a common precursor
and are synthesized concurrently.91,96 This feature may
contribute to differences in their actions at the endothelial interface
with the blood: PAF is specialized to signal leukocytes at the cell
surface, whereas PGI2 acts primarily in solution to retard
platelet aggregation and deposition. Both PGI2 and PAF also
elicit autocrine effects on ECs,91,92 which may be
important in modulating angiogenesis and controlling the synthesis of
EC-derived mediators.
PGI2 was the first endothelial-derived vascular smooth
muscle relaxing factor to be identified. PGI2, which was
generated locally, and PGI2 or its analogs, which were
infused systemically, caused vasodilatation and altered regional blood
flow.93 A receptor for PGI2, the
IP receptor, is present on vascular smooth muscle as well as on
platelets,97 consistent with early experimental observations, indicating that PGI2 acts principally to
modulate the function of these two cell types.98 Although
IP receptors are present in the arterial vascular wall,
PGI2 is not constitutively produced and does not appear to
regulate basal systemic vascular tone.99 Rather,
PGI2 synthesis is induced at sites of vascular perturbation, where it may regulate vasoconstriction and platelet deposition.66 Because of its effects on blood flow and
relevant cell-cell interactions, PGI2 may influence local
inflammatory responses as well. An important recent advance has been
the identification of prostaglandin H synthase-II (PHS-II), an
inducible form of a key enzyme in PGI2 formation providing
a mechanism by which the production of PGI2 and other
eicosanoids can be sustained in chronic states of inflammation and
vascular injury.
The receptor for PAF, the first receptor characterized at a molecular
level that recognizes a biologically-active lipid, is a member of the
serpentine G-protein-linked family (reviewed in Whatley et
al91). Intravascular infusion of PAF causes either vasodilatation or vasoconstriction, depending on the concentration administered, the time, and the specific vascular bed
studied.93 Some hemodynamic effects of PAF in vivo are
indirect and depend on the generation of eicosanoids or leukotrienes or
mediators derived from activated leukocytes or platelets and on cardiac effects.91-93 In shock and other in vivo pathologic states,
PAF acts concomitantly or sequentially with other classes of mediators, including leukotrienes and tumor necrosis factor-
(TNF-).90,91,100 As with PGI2,
it is unlikely that PAF is a circulating regulator of blood pressure
under basal conditions, despite early studies suggesting that PAF-like
activity is released from kidneys.92
| |
THE ROLE OF THE ENDOTHELIUM IN COAGULATION |
A crucial physiologic function of the endothelium is to facilitate
blood flow by providing an antithrombotic surface that inhibits
platelet adhesion and clotting. However, when the endothelium is
perturbed by physical forces or by specific chemical factors, the cells
undergo programmatic biochemical changes that culminate in their
transformation to a prothrombotic surface. A dynamic equilibrium exists
between these two states, modulated both at the level of gene
transcription and at the level of the intact cell, that often permits
the injured endothelium to return to its unperturbed state once the
procoagulant stimulus has dissipated (Table
2; see Bombeli et al101 for review). Although the fibrin clots formed as a consequence of procoagulant activity may serve a
protective organ function by limiting vascular damage induced by
trauma, infection, and inflammation, the loss of anticoagulant activity
may predispose to several common thrombotic disorders discussed in the
sections that follow.
Anticoagulant mechanisms.
Control of thrombin generation is a pivotal step in the balance between
the natural antithrombotic and the induced procoagulant activities of
the endothelium. Thrombin, a serine protease, serves diverse functions
in coagulation, including the activation of platelets, several
coagulation enzymes, and cofactors. Thrombin also stimulates
procoagulant pathways on the ECs themselves. Therefore, it is not
surprising that several highly regulated pathways have evolved to
constrain the generation and activity of thrombin (see Rosenberg and
Rosenberg102 for review), such that little enzyme activity
is found in the plasma of healthy individuals.103 The matrix surrounding the endothelium contains heparan sulfate and related
glycosaminoglycans (GAGs) that promote the activity of cell/matrix
associated antithrombin III (AT-III)104; the subendothelium
contains dermatan sulfate, which promotes the antithrombin activity of
heparin cofactor II.105 ECs also prevent thrombin formation
through the expression of tissue factor pathway inhibitor (TFPI), which
binds to factor Xa within the tissue-factor/VIIa/Xa complex (see
Broze106 for review). TFPI is released from its EC stores
by heparin. TFPI and AT-III both contribute to physiologic hemostasis
and can be depleted in acquired thrombotic states.107,108
The endothelium also helps to contain thrombin activity through the
expression of thrombomodulin (see Esmon and Fukudome109 for
review). Binding of thrombin to TM facilitates the enzyme's ability to
activate the anticoagulant protein C. In turn, the activity of
activated protein C (APC) is enhanced by its cofactor protein S, which
is synthesized by EC, among other cell types.110 ECs also
express receptors for APC111 that regulate the activity of
this pathway. APC, in turn, promotes the inactivation of activated
factors V and VIII. Binding of thrombin to TM also dampens the
enzyme's ability to activate platelets, factor V, factor XIII, and
fibrinogen and promotes EC fibrinolytic activity (see below). TM also
inhibits prothrombinase activity indirectly by binding factor
Xa.112 Thrombin bound to TM is rapidly endocytosed and
degraded.113 Various inflammatory cytokines downregulate TM
gene transcription and accelerate TM internalization114,115 while at the same time promote tissue factor expression (see below). Soluble TM is also shed into plasma and elevated plasma levels have
been identified in various disorders associated with EC injury (see
Cucurull and Gharavi116 and below).
Procoagulant mechanisms.
The pivotal step in transforming the EC membrane from an anticoagulant
to a procoagulant surface is the induction of tissue factor (TF). TF
dramatically accelerates factor VIIa-dependent activation of factors X
and IX, so it is not surprising that TF is not expressed by unperturbed
endothelium, at least in the adult organism.117
Interruption of the gene for TF is associated with impaired vascular
development and lethal embryonic bleeding,118-120 but the
source and function of TF during development have not been elucidated.
Synthesis of TF is induced in vitro by diverse agonists, including
thrombin, endotoxin, several cytokines, shear, hypoxia, oxidized
lipoproteins, and many other provocations (see Rapaport and
Rao121 and Nemerson122 for reviews).
Procoagulant activity is accelerated by exposure of anionic
phospholipids that may occur as a consequence of
apoptosis.108 TF is localized primarily beneath and between
cultured ECs,123 although some evidence for expression on
the cell surface has been presented.124 TF mRNA and protein
levels decline despite continued exposure to agonists, a mechanism that
may help contain the extent of fibrin formation. Cells in culture also
shed microvesicles containing TF,125 and plasma levels of
TF are elevated in patients with disseminated intravascular
coagulation,126 although the cellular source has not been
established. TF expression is rapidly induced after vascular injury,127 and TF is found associated with ECs within
atherosclerotic plaque128,129 and in tumor-derived
vessels.130 TF may also contribute to the regulation of
angiogenesis and tumor metastases through mechanisms independent of
coagulation.131,132 Yet, it has been difficult to
demonstrate expression of TF by ECs in vivo even in response to potent
provocations where expression was expected, another example of the
dissociation between the behavior of these cells in culture and that
seen in the whole organism.47
Once ECs expressing TF are exposed to plasma, prothrombinase activity
is generated and fibrin is formed on the surface of the
cells.133 This implies that ECs express binding sites for factors IX, IXa, X, and Xa; thrombin; and fibrin.134 Yet,
the identity and location of most of these binding sites is unknown, as
is their role in either physiologic hemostasis or in thrombosis. Factor
IX has recently been shown to bind type IV collagen in the EC
matrix,135 although its cellular association site promoting assembly of the intrinsic FX activation complex has not been
identified. Several candidate FX/Xa binding sites have been
reported,136,137 whereas others may be induced as a result
of exogenous stimuli.138 ECs also express receptors for
proteins of the contact factor pathway,139 but their role
in hemostasis is uncertain.
The most thoroughly characterized EC binding site for a coagulation
protein is the thrombin receptor, also termed the protease-activated receptor-1 (PAR1). The thrombin receptor is a high-affinity
G-protein-coupled protein140 that is activated when a
fragment derived from the amino terminus of the protein, formed as a
result of cleavage by thrombin, binds to the remaining cell-associated
receptor fragment. Binding of thrombin leads to a wide array of changes
in expression of prothrombotic and antithrombotic molecules by cultured
ECs, including TF, PAI-1, NO, PAF, ET, and PGI2, among
others (see Kanthou and Benzakour141 for review) and
disruption of cell-cell contacts (see Garcia et al142 for
review). Thrombin is also mitogenic for ECs, fibroblasts, and smooth
muscle cells and is chemotactic for monocytes.
The seemingly normal phenotype of surviving adult mice with targeted
disruptions in the thrombin receptor gene143 was
unanticipated and raised questions about the physiologic role of this
protein as well as other proteinase activated receptors expressed on
ECs.144 The subsequent discovery of two additional
protease-activated G-protein-coupled receptors, PAR-2 and PAR-3,
helped to explain this observation.145 Both PAR-1 and PAR-2
are present on some human ECs, whereas PAR-1, but not PAR-2, is
expressed on human platelets. PAR-3 is expressed by human bone marrow
and mouse megakaryocytes, but its expression on ECs has not been
established. Notable tissue- and species-specific differences in
expression and cellular distribution of PARs have been
described,145,146 making it difficult at present to relate
the phenotype of the various murine knockouts to human physiology.
ECs also express several receptors for fibrin and specific fibrin
degradation products,147 including a 130-kD
glycoprotein,148 a tissue transglutaminase,149
and the v3 integrin, although evidence
regarding their expression in vivo is only now
emerging.150,151 Binding of fibrin promotes EC adhesion,
spreading, proliferation, and migration; cell retraction; leukocyte
adhesion; and inhibition of PGI2 synthesis. Cultured ECs
also express glycoprotein Ib, which binds vWF secreted constitutively
by ECs and, presumably, the ultralarge vWF multimers released from
Weibel-Palade bodies in response to a number of agonists (see Wagner
and Bonfanti152 for review). Expression of GPIb by ECs
is enhanced by TNF-,153 but whether this glycoprotein
participates in the physiologic or pathophysiologic binding of vWF in
vivo requires additional study. The v3
integrin also binds vWF in the EC substratum. In vitro, conditions that
decrease v3 expression (TNF- plus interferon-
[IFN-] or arterial shear stress) increase GPIb expression,154 suggesting that the EC state may affect the
availability of adhesion receptors, although these finding require
confirmation in vivo.
Undoubtedly, additional receptors for coagulation proteins with
distinct functions will be characterized in the future. Genetic and
acquired alterations in the structure, expression, and function of
these EC receptors may contribute to hitherto unexplained hemorrhagic and thrombotic disorders. However, despite rather extensive study of EC
procoagulant function in culture, the extent to which platelet adherence or fibrin formation actually occurs on the surface of the
intact endothelium in vivo (as opposed to subendothelial matrix exposed
to blood) remains unclear. Perhaps the best indirect evidence comes
from animal models of Escherichia coli sepsis and cytokine infusion in which TF- and contact factor-dependent intravascular coagulation and multiorgan ischemic injury occurs in the absence of
overt EC disruption.155 Nevertheless, the contribution of endothelium, platelets, monocytes, and other cell types in these models
will require further study.
| |
ECs AND FIBRINOLYSIS |
Experiments using cultured ECs have yielded a concept that the
endothelial surface is profibrinolytic and thus helps maintain blood in
its fluid state.156 However, experiments using animal models have shown this conceptually satisfying hypothesis does not
accurately reflect the situation in vivo.42,157 It has also become clear that the contribution of ECs to fibrinolysis varies with
their metabolic status (ie, quiescent or activated), their vascular
derivation, and the concentration of other hemostatically active
molecules in the local plasma milieu.
Plasminogen activators.
Studies with ECs cultured from various tissues have led to the widely
held inference that t-PA production and secretion is a property of all
ECs.156 However, a few studies have gone largely unnoticed
in which PA activity, demonstrated by fibrin zymography, was observed
only in association with the adventitia and not with lumenal
ECs.157 More recent studies using in situ hybridization and
immunohistochemistry have demonstrated t-PA antigen and mRNA only in a
distinct subset of quiescent microvascular ECs of both primates and
mice.42,158 Hence, contrary to assumptions based on work
with cultured ECs, t-PA is associated only with a distinct subpopulation of the microvasculature, even after provocation. In both
murine brain and lung, the percentage of microvascular ECs producing
t-PA increases markedly upon exposure to pertinent stimuli; however, in
both cases, t-PA production remains an exclusive property of
microvascular ECs.42 Hence, invoking local EC production of
t-PA in large vessels as a mechanism of maintaining blood flow may not
adequately describe the in vivo situation.
t-PA production by cultured ECs is regulated by a variety of external
stimuli at the level of gene transcription and cellular release.159 Measurements of plasma t-PA levels suggest such
regulated production/secretion occurs in vivo as well.160
Intracellular signaling pathways operative in stimulated t-PA release
have been described in vitro.161 The mechanisms that
control EC t-PA production in vivo are less well understood, but
clearly such regulation occurs.162 Humans exhibit higher
plasma levels of t-PA after exercise or venous compression, but the
cellular source of this increase has not been
established.161
The other mammalian PA, u-PA, appears not to be produced by most
quiescent ECs.43 Rather, it is expressed by ECs involved in
wound repair or angiogenesis,163 consistent with the
hypothesized importance of u-PA in cell migration and tissue
remodeling. Yet, u-PA is obviously important to vascular homeostasis,
because mice genetically deficient in u-PA develop inflammation induced
thrombi164 and manifest thrombotic tissue injury in
response to lipopolysaccharide (LPS).165
However, the extrarenal source of u-PA in physiologic states has not
been established.
PA receptors.
The presence of EC receptors for t-PA has been reported by several
groups.166-171 Binding of t-PA to ECs has been reported to promote its fibrinolytic activity166,172 and to stimulate
cell proliferation.173 Recently, one such t-PA binding site
has been identified as annexin II, which is expressed on
ECs174 and binds t-PA in a specific and saturable manner in
vitro.172 However, the expression of annexin II on the
endothelium in vivo has not yet been demonstrated.
The u-PA receptor (u-PAR) expressed by ECs appears identical to that
expressed on other cell types.175,176 u-PAR is a
three-domain protein linked to cell surfaces by a glycerophosphatidyl
inositol anchor. Single-chain u-PA (the form found in
plasma177) bound to cells via u-PAR exhibits increased
plasminogen activating efficiency175,178 and is relatively
protected from inhibition by PAI-1 and PAI-2.179,180 u-PAR
may be expressed primarily on the surface of migrating ECs participating in angiogenesis, rather than on quiescent ECs lining normal vessels.181 Mice genetically lacking u-PAR develop
normally and do not exhibit spontaneous vascular
occlusion.182 Hence, u-PAR has yet to be shown to
participate in maintaining physiologic blood fluidity, although it may
be important in vascular repair.
Cells express diverse binding sites for plasminogen, among which are
proteins that exhibit a carboxyterminal lysine (see Plow et
al35 for review). Plasminogen binds to ECs in vitro with an
affinity that would predict receptor occupancy at physiologic plasma
concentrations.183 Cell-associated plasmin may be
relatively protected from inhibition by 2-plasmin
inhibitor.184 However, the exact identity of these EC
plasminogen binding sites remains uncertain and their expression in
vivo has not been established.185 Lp(a) competes for the
binding of plasminogen to ECs,186 which may contribute to
the prothrombotic effects of this lipoprotein.187
Plasminogen activator inhibitors (PAIs).
ECs in culture produce abundant PAI-1 that is associated primarily with
its extracellular matrix, resulting in stabilization of its
activity.188 PAI-1 synthesis is stimulated by numerous agents, including thrombin, endotoxin, various cytokines, Lp(a), and
oxidized LDL, among others.189 Yet, experiments in mice
have shown that liver is the major source of plasma PAI-1 and that quiescent EC express little or no inhibitor.190 However,
after exposure to inflammatory stimuli, ECs in virtually every tissue express PAI-1.190 PAI-2 is found normally in plasma only
during pregnancy191 and is not synthesized by ECs to an
appreciable extent. However, multiply passaged ECs express PAI-2 in
response to some agonists that may point to a local effect in select
settings.192 PAI-3 (also known as the protein C inhibitor)
has a much lower affinity for u-PA and t-PA than does PAI-1, but it is
present in plasma at much higher concentrations.193
Production of PAI-3 by ECs has not been reported, but PAI-3 antigen can
bind to heparan sulfate proteoglycan on the lumenal surface of ECs,
thereby increasing its activity.194
Thrombomodulin.
Binding of thrombin to thrombomodulin (see "The Role of the
Endothelium in Coagulation" above) accelerates its capacity to activate a protein known as thrombin-activatable fibrinolysis inhibitor
(TAFI).195 TAFI is a procarboxypeptidase-B-like molecule that, when activated, cleaves basic carboxyterminal residues within fibrin and other proteins. This results in the loss of
plasminogen/plasmin and t-PA binding sites on fibrin such that
fibrinolysis is retarded.195 Thus, through the regulated
expression of thrombomodulin, ECs serve as potent templates to decrease
the rate of intravascular fibrinolysis.
Although a simple balance between profibrinolytic (PAs) and
antifibrinolytic (PAIs) pathways seemed an attractive mechanism to
explain the clinical experience that unperturbed endothelium helps
maintain blood fluidity, more recent in vivo data have shown that the
mechanism may not be quite so straightforward. Indeed, ECs seem to
express more antifibrinolytic than profibrinolytic activity in many
settings studied to date. Clearly, more work will be required to
clarify the contribution of quiescent and activated ECs to
fibrinolysis.
Summary.
The first part of this two part series has focused on the development
of the vasculature and the physiological functions of the endothelium
as a gate-keeper regulating blood flow and hemostasis. Current insights
into the generally unappreciated heterogeneity of endothelium from
different vascular sites have been noted as potential discrepancies
between the quiescent state of the endothelium in vivo and the behavior
of these cells in culture. The second part of this review will
concentrate on the mechanism by which the endothelium contributes to
cell trafficking and the impact of endothelial injury on the
development of several common human vascular disorders.
| |
PART II |
The endothelium, positioned at the interface between blood and tissue,
is equipped to respond quickly to local changes in biological needs
caused by trauma or inflammation. In the first part of this review, the
capacity of the endothelium to move rapidly between an antithrombotic
and prothrombotic state was discussed. In this second part, the
mechanisms by which the endothelium regulates the trafficking of the
cellular elements of the blood will be considered first, after which
the impact of EC dysfunction on the pathogenesis of several common
vascular disorders will be reviewed.
| |
INTERACTION BETWEEN ECs AND BLOOD CELLS |
In addition to the above-mentioned contribution of the endothelium to
regulating blood coagulation, ECs also express cell surface-molecules
that orchestrate the trafficking of circulating blood cells. These
cell-associated molecules help direct the migration of leukocytes into
specific organs under physiologic conditions and accelerate migration
towards sites of inflammation, eg, in response to IL-6196
or IL-8,197 among many others. Recently, these pathways
have also been implicated in the adhesion of platelets and erythrocytes
in several common disorders associated with vascular occlusion.
Interactions of platelets and leukocytes with the vessel wall.
Flowing leukocytes and platelets may adhere to specific regions of the
endothelium, to exposed subendothelial components, or to each other
during the process of immune surveillance as well as in response to
tissue injury or infection. These multicellular interactions are
essential precursors of physiologic inflammation and hemostasis.
Conversely, uncontrolled adhesion of leukocytes and platelets
contributes to inflammatory and thrombotic disorders. Under shear
forces, both platelets and leukocytes interact with vessel surfaces
through a multistep process that includes (1) initial formation of
usually reversible attachments; (2) activation of the attached cells;
(3) development of stronger, shear-resistant adhesion; and (4)
spreading, emigration, and other sequelae
(Fig 3).
View larger version (17K):
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[in a new window]
| Fig 3.
Physiologic interaction of leukocytes with the
endothelium. Leukocyte adhesion and transmigration occurs during
inflammation, usually at the postcapillary venules where shear stress
is lowest.
|
|
Platelet adhesion during hemostasis.
Circulating platelets normally do not interact with the EC surface (see
Schafer198 for review), in part due to the release of
PGI2, the release of NO, and the recently described
expression of an Ecto-ADPase (CD39).199 However, during
hemorrhage, platelets adhere avidly to exposed subendothelial
components, where they are rapidly activated. Circulating platelets
interact with the adherent platelets, producing a hemostatic plug that
promotes thrombin generation and development of a stable fibrin clot.
Platelets adhere particularly efficiently to the subendothelium under
high shear stress, accounting for the greater number of platelets in fibrin clots within arteries compared with those within
veins.200
Under the influence of arterial shear stress, unactivated platelets
attach first to the subendothelium through interactions of the platelet
glycoprotein (GP) Ib-IX-V complex with immobilized vWF, a large,
multimeric protein with binding sites for several other molecules,
including subendothelial collagen.201 The GPIb-IX-V complex
consists of four proteins, each with one or more leucine-rich repeats:
the disulfide-linked GPIb and GPIb and the noncovalently associated GPIX and GPV. The binding site for vWF is located on GPIb, between the amino-terminal leucine-rich repeats and the membrane-proximal O-glycan-rich domain. The region includes clustered tyrosines that must be sulfated for GPIb to bind vWF.202
GPIb binds weakly to plasma vWF, but with high activity to
immobilized vWF under conditions of high shear stress, which may favor
binding by altering the conformation of GPIb and/or
vWF.200,203 Flowing platelets attach transiently to vWF,
resulting in continuous movement of the cells along the
surface.204 Such cellular interactions require very fast
molecular rates for attachment and detachment; the fast dissociation
rates are not significantly accelerated by shear stresses for
detachment. Under the lower shear stresses found in veins, unactivated
platelets use the integrin IIb3 to attach
to and immediately arrest on immobilized fibrinogen.204 Under low shear conditions, platelets may also use integrins or other
molecules to attach to subendothelial matrix components, such as
fibronectin, laminin, and thrombospondin.205
Once platelets adhere to either vWF or fibrinogen, they are activated
by secreted products such as ADP or epinephrine or by surface
molecules, such as collagen, that cross-link the integrin 21 and other platelet receptors. The
activated platelets spread and adhere more avidly to the subendothelial
surface, principally through binding of activated
IIb3 to fibrinogen, which recruits additional platelets into aggregates206; platelet
IIb3 also binds to a distinct site on
vWF.201 Shear-resistant adhesion may be further enhanced by
interactions of other integrins or receptors with laminin, fibronectin,
and thrombospondin.200 As thrombin is generated, converting
bound fibrinogen to fibrin, the aggregated platelets contract to
strengthen the clot. Signaling through adhesion receptors, particularly
integrins, may regulate the cytoskeletal-protein redistributions
required for clot retraction.206 Increased bleeding is
observed in patients with inherited defects in molecules that mediate
platelet adhesion such as Bernard-Soulier disease
(absence/dysfunction of GPIb-IX-V) and Glanzmann's thrombasthenia (absence/dysfunction of IIb3), confirming
their physiological function.203
Leukocyte adhesion during inflammation.
During inflammation, leukocytes tether to and roll on the EC surface.
The cells then arrest, spread, and finally emigrate between ECs to
reach the underlying tissues. Unlike platelets, which typically attach
to the subendothelium of arteries under high shear stresses, leukocytes
usually attach to the ECs, where shear stresses are lowest, in the
lining postcapillary venules.
In most circumstances, interactions with selectins, transmembrane
glycoproteins that recognize cell-surface carbohydrate ligands found on
leukocytes, initiate and mediate tethering and rolling of leukocytes on
the EC surface.207 Selectins constitute a family of three
known molecules, each of which has an amino-terminal Ca2+-dependent lectin domain, an EGF domain, a series of
short consensus repeats, a transmembrane domain, and a cytoplasmic
tail. L-selectin is expressed on most leukocytes and binds to ligands
constitutively expressed on high endothelial venules of lymphoid
tissues, to ligands induced on endothelium at sites of inflammation,
and to ligands exposed on other leukocytes. E-selectin is expressed on activated ECs and leukocytes. P-selectin is rapidly redistributed from
secretory granules to the surface of platelets and ECs stimulated with
thrombin or other secretagogues. Like E-selectin, P-selectin binds to
ligands on leukocytes. Leukocytes adherent to the endothelium can make
contact with flowing leukocytes through the L-selectin molecule,
resulting in amplification of leukocyte recruitment to sites of
inflammation.208 At sites of hemorrhage, leukocytes tether
to and roll on adherent platelets.209 Monocytes recruited in this manner may augment fibrin generation, perhaps by elaborating tissue factor after their activation.210 Selectin ligands
expressed on high endothelial venules also mediate rolling of activated platelets and enhance accumulation of lymphocytes in lymph
nodes.211 Thus, selectins initiate inflammatory, immune,
and hemostatic responses by promoting transient multicellular
interactions under conditions of shear stress.
The selectins bind weakly to sialylated and fucosylated
oligosaccharides, such as sialyl Lewis x, a terminal component of glycans attached to many proteins and lipids on most leukocytes and
some ECs. Strikingly, the selectins bind with higher affinity to only a
few sialylated and fucosylated glycoproteins on target cells.207 E-selectin binds preferentially to ESL-1, a
protein with at most five N-glycans and no described O-
glycans. L-selectin and P-selectin bind preferentially to
sialomucins whose recognition requires sulfation as well as
sialylation and fucosylation. The sulfate esters are attached to
O-glycans on GlyCAM-1, a ligand for L-selectin secreted by high
endothelial venules.212 In contrast, the sulfate esters are
attached to tyrosines near the amino terminus of PSGL-1, a ligand for
selectins on leukocytes.213 Construction of some glycans
may be restricted to specific sites on the polypeptide backbone of only
a few proteins.214 Of the described glycoprotein ligands
for selectins, only PSGL-1, a ligand for selectins on leukocytes, has
been shown to mediate cell-cell interactions under shear conditions
(reviewed in McEver and Cummings215). The
41 and 47
integrins, which are expressed on mononuclear cells and eosinophils,
but not on neutrophils, also mediate tethering and rolling and
occasionally arrest the flow of leukocytes on ECs by binding to the
Ig-ligands VCAM-1 and MAdCAM-1.216,217 Some lymphocytes use
CD44 to roll on hyaluronate-bearing surfaces.218
Under hydrodynamic flow, cell tethering and rolling requires bonds with
sufficient mechanical strength between adhesion molecules and rapid
rates of association and dissociation.219 Interestingly, attachment of leukocytes through selectins requires a threshold hydrodynamic shear force that may prevent leukocyte aggregation in
regions of low flow.220 A higher shear threshold for
L-selectin may reflect faster dissociation rates of L-selectin ligand
bonds220 and/or adhesion-induced shedding of
L-selectin from the cell surface.221 Because L-selectin,
PSGL-1, and 4 integrins are concentrated on the tips of
the leukocyte microvilli, the probability of rapid contact with PSGL-1
is increased and the repulsion is minimized between the charged
glycocalyces of apposing cells.222
The slow velocities of rolling leukocytes favor encounters with
chemokines or lipid autacoids presented at or near the apical surface
of the endothelium. These mediators transduce signals that cooperate
with those produced by engagement of L-selectin or PSGL-1 to activate
the leukocytes.223 This crucial activation event, coupled
with the slow rolling velocities, enables the 2 integrins on leukocytes to bind to Ig ligands such as ICAM-1 and ICAM-2
on the EC surfaces.224 Plasma fibrinogen also links
leukocytes to the endothelium by binding simultaneously to
M2 and ICAM-1,225 two
integrins on the vessel wall that provide shear-resistant attachments.
Subsequently, leukocytes migrate between ECs into tissues by mechanisms
that are not completely understood but are affected by gradients of
chemokines with restricted specificities,49 1 and 2 integrins activation states, and
homotypic interactions with the Ig-like receptor,
PECAM-1.226 This may require disruption of homotypic
interaction of cadherins at endothelial tight junctions.227
Leukocyte recruitment to lymphoid tissues or inflammatory sites
requires the coordinated expression of specific combinations of
adhesion and signaling molecules. Diversity at each step of the
multistep cascade ensures that the appropriate leukocytes accumulate
for a restricted period in response to a specific
challenge.49,224 Absence of P-selectin delays fatty streak
formation in mice predisposed to developing atherosclerotic
lesions.228 On the other hand, increased numbers of
infections are observed in patients who are congenitally deficient in
2 integrins229 or in fucosylated ligands for
selectins,230 confirming the physiologic significance of these molecules in immune and inflammatory responses. Increased susceptibility to infection combined with impaired leukocyte
accumulation in mice rendered genetically deficient in
selectins,231-234 in fucosyltransferases,235 in
ICAM-1,236-239 or in 4
integrins240 further support the overlapping functions of
these molecules.
Endothelium in cell-mediated immunity (CMI).
CMI is defined as the protective set of immune reactions that can be
adoptively transferred from a sensitized individual to an unimmunized
host by a subset of T lymphocytes but not by antibodies. Vascular ECs
may play two important roles in the evolution of CMI reactions: (1)
antigen presentation to T cells (reviewed in Pober et
al241) and (2) recruitment of inflammatory
cells.49 Recall responses such as CMI reactions develop
directly in peripheral tissues in which circulating memory T cells are
activated by antigen presented on the surface of a resident cell
population. This is in contrast to primary immunity that begins in the
secondary lymphoid organs such as lymph node or spleen, where naive T
cells encounter antigen on the surface of a specialized
antigen-presenting cell. Once effector and memory cells develop in a
secondary lymphoid organ, they may emigrate to the peripheral site via
the blood stream, where reactivation by the antigenic stimulus is
possible.
The two cell types that may present antigen to specific T cells in
peripheral tissues are macrophages, resident in the tissues, or local
microvascular ECs. In vitro, cultured human ECs from a variety of
vascular beds constitutively express class I MHC molecules (used to
present peptides derived from foreign proteins to CD8+ T
cells). IFN- can induce ECs to express class II MHC molecules (used
to present peptides derived from foreign proteins to CD4+ T
cells). There is only limited information on antigen processing by
cultured ECs, but indirect evidence (ie, the formation of functional peptide-MHC molecule complexes that can be recognized by cultured T-cell lines) suggests that EC are fully competent to perform this
function. In vivo, microvascular ECs constitutively express both class
I and class II MHC molecules, although the levels of both molecules can
be increased further by cytokines (eg, IFN-).
How do ECs compare with tissue macrophages as antigen-presenting cells?
This has been a difficult question to address experimentally in humans
because the relevant cell populations (ie, ECs, macrophages, and T
cells) are not readily isolated from one immunized individual. A
commonly used indirect approach is to examine the response of T cells
isolated from one donor to cultured ECs and monocytes isolated from a
second donor. This allogeneic response of T cells is directed against
complexes formed between peptides associated with allogeneic MHC
molecules and results from a cross-reaction of T cells that are
specific for a foreign peptide associated with a self MHC molecule; it
is an excellent model of normal immunity that avoids the requirement
for isolating ECs from immunized donors. ECs activate about one fifth
as many allogeneic T cells (either CD8+ or
CD4+) as monocytes, determined in limiting dilution
analyses for production of IL-2. Some of this difference may arise from
a larger number of different peptide-MHC molecule complexes displayed
on freshly isolated monocytes compared with serially cultured ECs, but
a critical contribution to this difference is that monocytes can activate both naive and memory T cells, whereas ECs can only activate memory T cells.242 It has recently been reported that ECs
actually make naive T cells unresponsive to stimulation (ie, induce
clonal anergy).243 The ability of ECs to activate memory
but not naive T cells in vitro is consistent with a role in
presentation of antigen as an initiating event in CMI, which is a
memory T-cell response.
The differences in ability among cell types to activate resting naive
or memory T cells are best explained by differences in expression of
cell surface ligands, called costimulators, that provide
antigen-independent signals that complement those provided by T-cell
antigen-dependent recognition.241 Human ECs primarily provide costimulation to T cells through LFA-3 (CD58), which interacts with T-cell CD2. Monocytes and other professional antigen-presenting cells additionally provide costimulation to T cells through B7.1 (CD80)
or B7.2 (CD86), which interact with T-cell CD28. Surprisingly, pig ECs
express B7.2 and, more remarkably, pig B7.2 can functionally costimulate human T cells through CD28, a potential problem facing those who wish to use pigs as organ donors in human
transplantation.244
The recruitment of inflammatory cells is the second role played by ECs
in CMI. Once memory T cells become activated by antigens, they, in
turn, can activate a variety of EC functions that contribute to
recruitment of inflammatory cells. The signals provided by T cells to
activate ECs may involve contact-dependent signals (eg, T-cell CD40
ligand may engage EC CD40)245 or cytokines (eg, T-cell-secreted TNF/LT, IFN-, or IL-4 may act on the EC; reviewed in Pober and Cotran246). Several different responses of ECs
to these signals contribute to inflammation, including production of
vasodilators to increase delivery of leukocytes to the tissue, expression of adhesion molecules that tether and bind circulating leukocytes, synthesis of chemokines that contribute to transendothelial migration, and leakage of plasma proteins that form a provisional matrix in tissues for migration of extravasated leukocytes (reviewed in
Pober and Cotran247).
The expression of various adhesion molecules on the endothelial surface
changes over time, favoring neutrophil recruitment initially (eg,
dependent on E-selectin expression) and recruitment of other leukocytes
at later times (eg, dependent on VCAM-1 expression). The
identity of chemokines may also change over time from synthesis of
neutrophil-activating C-X-C chemokines early on to the subsequent synthesis of C-C chemokines that act on other leukocytes. The net
result is that the composition of infiltrates change over time from
neutrophil-rich to T-cell-rich and monocyte-rich delayed hypersensitivity (DTH) reactions or to T-cell-rich, eosinophil-rich, and basophil-rich late-phase reactions. The differences between DTH and
late-phase inflammation appear to be attributable to local production
of IFN- versus IL-4 and IL-5, respectively. The T cells recruited in
DTH reactions are predominantly Th1-like cells (that mediate DTH),
whereas those in late-phase reactions are predominantly Th2-like cells
(that mediate late-phase reactions). The selective recruitment of Th1
cells into DTH reactions may be mediated by E-selectins and
P-selectins.248 Interestingly, although Th1 and Th2 cells
appear to express equivalent levels of PSGL-1, only Th1 cells are able
to bind P-selectin.249
Once infiltrates develop, a cytokine-rich milieu is generated that is
sustained until the antigen is eliminated. Such chronic cytokine
exposure has effects on ECs not seen at early times. For example, over
the first few days, adhesion molecules that are initially expressed
diffusely on the lumenal surface redistribute to inter-EC
junctions.250 The basement membrane becomes enriched in
sulfated glycosaminoglycans,251 and the cells assume an
altered morphology characteristic of endothelium at sites of high
lymphocyte extravasation, such as the high endothelial venules of lymph
nodes.252 These features may promote leukocyte
extravasation in acute settings. More chronic CMI reactions result in
angiogenesis and tissue remodeling.
In general, CMI reactions do not produce endothelial injury, perhaps
because T cells efficiently focus the response on the source of
antigen, microbe-infected cells. An exception may be instances in which
ECs are themselves infected by intracellular microbes (eg, viruses), so
that cytolytic T lymphocytes (CTLs) kill the infected endothelium.
Endothelial injury may also develop in transplantation, in which the
immune system may perceive engrafted cells as self-cells that have been
infected by virus. Some of the peptides recognized by graft-rejecting
CTLs in association with allogeneic MHC molecules may be EC-specific
and not found on leukocytes.253 In these instances, the CTL
response may be directed at the endothelium. In addition, endothelium
may be killed when CTL or natural killer (NK) cells are overstimulated
by cytokines and lose their specificity. The actions of such
lymphokine-activated killer (LAK) cells may contribute to the vascular
leak syndrome associated with IL-2 or LAK therapy in cancer
patients.254 It is increasingly appreciated that ECs may
actively resist immune-mediated injury and that several of the
resistance mechanisms involve cytokine-inducible genes.255
Thus, the CMI response itself may protect ECs if the onset is
sufficiently gradual (or if it is delayed by immunosuppression), so
that the cells have had adequate time to acquire the resistant phenotype.
Erythrocyte-endothelial adherence.
Interactions between the endothelium and erythrocytes may contribute to
the vascular complications of sickle cell anemia (SSA),256 infection with Plasmodium falciparum malaria,257
and diabetes.258 Red blood cell (RBC) adherence may
initiate or promote intravascular sludging and occlusion leading to
ischemic tissue and organ damage, retinopathy, dermal ulcers, strokes,
and other infarctive pathologies. RBC adherence is dependent on EC
surface molecules and is modulated by local hemodynamic factors.
Recently, some of the RBC receptors, EC adhesion molecules, cytokines,
and other vaso-active substances involved in adherence have been
identified.
Sickle cell anemia.
Although the tendency for hemoglobin SS to polymerize at low oxygen
tension is assumed to be the dominant factor in the pathogenesis of
occlusive pain episodes, morphologic evidence of sickling is not seen
immediately after hemoglobin is deoxygenated.259 Rather, adherence of SS-RBCs to vascular endothelium, which retards transit through the microvasculature, may be an important initiating event in
this cascade.260,261 Adherence of SS-RBCs in vitro is
sufficiently strong to withstand fluid shear forces typical of those
seen in postcapillary venules.262 The resultant delay in
capillary transit may allow time for sickle cells containing
deoxygenated hemoglobin to deform leading to stable vascular
obstruction263 and the resultant development of painful
crises.
Adherence of SS-RBCs appears to result not only from the intrinsic
membrane abnormalities induced in the erythrocytes, but also as a
result of specific plasma factors and the state of EC activation
(reviewed in Wick and Eckman264). For example, plasma from
patients with SSA promotes RBC adherence in excess of that seen with
normal plasma,265,266 and plasma collected during painful crises promotes adherence to an even greater extent.265
Fibrinogen,265 fibronectin,262
vWF,262 and thrombospondin267,268 have all been
identified as factors in plasma that modulate SS-RBC adhesion.
Several adherence pathways have been described in vitro, including (1)
bridging of GPIb-like molecules on sickle cells with their cognate
receptors on ECs by unusually large vWF multimers released from
activated platelets or by the stimulated endothelium itself262; (2) bridging by thrombospondin via CD36 on
sickle reticulocytes269 and the
v3 integrin on large vessel
ECs267 or v3 and CD36 on
microvascular endothelium268; (3) binding of sickle
reticulocytes via 41
receptors269,270 to VCAM-1 expressed on ECs stimulated by
cytokines270,271 or by double-stranded RNA272;
(4) binding of sickle reticulocyte via 41
activated by phorbol ester or IL-8 to EC-associated
fibronectin273; and (5) binding of SS-RBCs to E-selectin
expressed on ECs stimulated by IL-1.274 The expression
of VLA-4 and CD36 on reticulocytes from sickle cell patients is reduced
by treatment with hydroxyurea.275 However, the precise
contribution of each of these or additional pathways to SS-RBC
adherence in vivo requires further study.
In vitro, adherence of sickled RBCs to large venous vessels differs
both qualitatively and quantitatively from adherence to microvascular
endothelium.276 High molecular weight vWF multimers promote
greater adherence to venous than to microvascular
endothelium.276 Autologous plasma promotes greater
adherence of sickle RBCs to microvascular endothelium than does plasma
from individuals without SS disease.276 Sickle cell
adherence is localized to postcapillary venules in ex vivo tissue
perfusion studies, with no adherence observed in either capillaries or
arterioles.263 These differences are likely due, at least
in part, to variation in the expression of adhesion molecules and their
receptors on the vasculature (see, eg, Swerlick et al277).
Sickle cell adherence is also dependent on local hemodynamic conditions
(reviewed in Wick and Eckman264). Under static conditions, the dense SS-RBCs adhere most avidly, possibly due to intrinsic membrane alterations.261 In contrast, the least-dense
sickle cells and reticulocytes are most adherent to the endothelium in vitro270,273,274 and ex vivo under flow
conditions.230 Sickle cell adherence under flow is also
more tenacious than under static conditions.278 Thus,
adherence of reticulocytes expressing adhesion receptors may dominate
in vivo in situations in which flow is maintained.264
Adherence and trapping of membrane-damaged sickled erythrocytes may
follow once flow has been further impeded, ultimately leading to
complete vascular occlusion.279
Painful crises frequently accompany ischemia, infarction, infection, or
inflammation, situations in which the coagulation cascade may be
activated as well.256 Activation of leukocytes and/or platelets may result in the generation and release of
cytokines, adhesive proteins, or other factors that modulate
endothelial or sickle cell adhesivity. Observations that activation of
sickle cells273 and ECs with cytokines,270
virus,272 or thrombogenic plasma
proteins262,265,267,268 promotes RBC adherence suggests a
mechanism by which infection and inflammation may initiate or propagate
vaso-occlusion and episodic pain. Presumably, sickle cell adherence in
vivo is most extensive at sites where the relevant adherence molecules
are expressed most highly and shear stresses are sufficiently low to
permit binding.264 Adherence of sickle cells may alter
their metabolism,280 promote leukocyte
adhesion,281 and contribute to their
desquemation.281
Malaria.
Plasmodium falciparum causes cerebral manifestations, perhaps
the most serious complication of malaria. Maturation of the parasite
within host RBCs induces membrane changes which promote adherence to
cerebral microvascular endothelium in vitro and may lead to vascular
congestion and hypoxia in vivo.257 It has been proposed
that cytoadherence provides selective advantage to the invading
parasites by facilitating their growth under the conditions of reduced
oxygen tension found in the cerebral microcirculation and by enabling
parasitized RBCs to avoid splenic filtration.257
Parasitized RBCs bind to cell surface molecules on ECs, including
CD36,257 ICAM-1,257 VCAM-1,282 and
E-selectin.282 Additionally, thrombospondin allows bridging
between parasitized RBCs and CD36 receptors on ECs.257 The
various endothelial receptors act synergistically to slow and arrest
parasitized RBCs under flow conditions and at shear stresses in the
physiological range.283,284 Additional binding sites for
parasitized RBCs may be induced as a consequence of the inflammatory
response to Plasmodium falciparum infection257 due
to leukocyte activation,285 cytokine
release,286 and EC activation.285
Binding to the endothelium occurs through knobs on RBCs induced by the
parasite. These knobs contain Plasmodium falciparum erythrocyte
membrane protein 1 that appears to participate in this
process.257 Cytoadherence is inhibited by peptide fragments of the erythrocyte band 3 protein287 and by monoclonal
antibodies that recognize band 3 on RBCs infected with mature
parasites, suggesting involvement of cryptic regions of the protein
exposed or altered during the course of infection.288 It
has also been reported that some field isolates of Plasmodium
falciparum promote adherence to chondroitin sulfate
A.289 These data provide additional opportunities for
antimalarial therapy based on inhibition of interactions between
parasitized RBCs and ECs.
Diabetes mellitus.
Erythrocytes from patients with diabetes mellitus are more adherent to
normal ECs than are RBCs from healthy donors.290 The extent
of adhesion correlates with the severity of vascular
complications290; greater adherence is observed in the
absence of plasma,266 suggesting a defect intrinsic to the
RBC. Adhesion is augmented further by plasma from diabetic patients as
well as by fibrinogen,258 suggesting a mechanism by which
acute-phase reactants may modulate vascular obstruction. Persistent
exposure to hyperglycemia induces the formation of advanced glycation
end products (AGEs) that modify structures on erythrocyte. AGE
modification of erythrocytes allows them to engage a specific receptor,
RAGE, (receptor for advanced glycation endproducts), which has been
identified immunohistochemically and by in situ hybridization in the
vasculature in vivo.258 Exposure of RBCs harvested from
patients with diabetes to cultured endothelium results in increased
adherence compared with those from euglycemic individuals due to
erythrocyte-associated AGEs binding to endothelial RAGE.258
Furthermore, it has been hypothesized that interaction of diabetic
erythrocytes with endothelium through an AGE/RAGE linkage may promote
oxidant stress leading to EC activation (see below).
| |
EC PERTURBATION AND VASCULAR DISEASE |
It is currently believed that endothelium must remain in a resting or
unperturbed state to optimize expression of anticoagulant activities
which prevent thrombus formation (see "The Role of the Endothelium
in Coagulation" above). However, the endothelium is a dynamic organ
that responds to an array of agonists and environmental challenges by
undergoing an activation process not unlike that of platelets, which
eventuates in the loss of anticoagulant properties and/or
acquisition of procoagulant function. Although the role of the
endothelium in the pathogenesis of thrombosis in vivo remains unproven,
accumulating evidence points towards dysregulation of EC function as
pivotal in the development of several important thrombotic disorders.
Plasma factors such as antibodies or lipoproteins that perturb EC
function in vitro have been identified. It is likely that genetic
differences in EC responsiveness to environmental pressures will be
uncovered as contributors to the development of other common vascular
diseases.
The endothelium in atherosclerosis.
Atherosclerosis is the most prevalent vascular disease in developed
countries. The concept that atherosclerosis arises in response to
endothelial injury was first proposed more than 20 years ago, when it
was appreciated that irregularities in EC organization are often found
overlying early fatty streaks, whereas overt endothelial denudation is
seen only in the late stages of the disease (see Ross and
Glomset291 for review; Fig 4).
There is now extensive evidence that this morphologically abnormal
endothelium is also dysfunctional and actually contributes to the
propagation of lesions (see Ross292 and McGorisk and
Treasure293 for reviews). These findings not only provide
insight into the pathogenesis of atherosclerosis, but also suggest
means to monitor the progression of lesions and effectiveness of
treatment.
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| Fig 4.
Very early development of atherosclerosis in a nonhuman
primate. The focal origin of atherosclerosis is apparent beneath an intact endothelium. Scanning electron microscopy of ECs outlined by
silver deposition in a thoracic aorta (photograph courtesy of Peter F. Davies, PhD, Institute for Medicine and Engineering, University of
Pennsylvania, Philadelphia, PA).
|
|
Atherosclerosis is a multifactorial disease with numerous predisposing
factors, including smoking, diabetes, hyperlipidemia, hypertension,
mechanical stress, and inflammation. Such diverse and complex processes
may perturb EC function through a common pathway. Alternatively, the
endothelium may react to diverse stimuli with a limited repertoire of
reparative, but ultimately dysfunctional, responses.
Oxidant stress.
Oxidant stress has been proposed as a mechanism common to diverse
injuries such as unsaturated lipids that can be converted to cytotoxic
lipid peroxidation products, various chemicals, radiation, and reactive
oxygen metabolites released by leukocytes that migrate into the
vasculature in response to infection and autoimmune injury. The
pathways involved in the initiation and control of oxidant injury are
receiving considerable study. Oxidized LDL and its peroxide derivative
lysophosphatidylcholine stimulate protein kinase C activity,
phosphoinositide turnover, and release of internal calcium; impair EC
replication and angiogenesis; and induce apoptosis (reviewed in
Henry294). Cytokines, such as TNF-, can both induce reactive oxygen species in ECs and stimulate the ubiquitous
transcription factor NF-
B, resulting in a transcriptional activation
of other proatherogenic molecules such as VCAM-1 (reviewed in Larrick
and Wright295). Oxidation reactions also promote the
formation of AGEs that contribute to diabetic vasculopathy (reviewed in
Schmidt et al296) and initiate transcriptional activation
of VCAM-1297 and monocyte chemotactic protein-1 (MCP-1),
which promotes monocyte entry into the vessel wall (reviewed in
Gimbrone298).
Shear stress.
ECs are exposed continuously to fluid shear stresses that lead to a
dynamic interaction between the cell and the substratum via focal
contact sites. Shear-induced changes in transduced biomechanical forces
can cause not only cytoskeletal rearrangement and altered morphology
but changes in endothelial gene expression299,300 (Fig 5). Most studies have examined
primarily changes that occur within hours of initiating flow, which may
best reflect the situation in vascular beds exposed to newly flowing
blood such as postangioplasty, but the adaptive response of endothelium
to shear forces is less well characterized.
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| Fig 5.
EC alignment by directional steady flow in vitro
(photographs courtesy of Peter F. Davies, PhD, Institute
for Medicine and Engineering, University of Pennsylvania, Philadelphia,
PA). (A) Before exposure to shear stress (no flow). (B) Twenty-four
hours after exposure to flow (shear stress, 10 dynes/cm2).
|
|
An effect of shear on vascular biology is suggested by the observation,
eg, of decreased vasodilator function at coronary branch points that
have a predilection for atherosclerosis.301 Consistent with
this notion, a number of genes relevant to the development of
atherosclerosis expressed by ECs have shear stress response elements
that coordinate their induction. Shear modulates EC production of
products regulating vasoconstriction (NO, endothelin-1), vessel growth
(FGF, platelet derived growth factor [PDGF]-A and -B, and
TGF-), fibrinolysis (t-PA), and cell adhesion (MCP-1, VCAM-1, and
ICAM-1) (see Malek and Izumo,300 Ando and
Kamiya,302 and Tsao et al303 for reviews).
Shear has been reported to modulate the expression of thrombomodulin in
a reversible manner299 and abrogate cytokine-induced EC
tissue factor expression.304
The mechanism(s) responsible for the modulation of gene expression by
shear is under study. At least part of these shear-induced effects are
mediated through modulation of gene transcription. A number of genes,
such as PDGF-B, contain one or more shear stress responsive elements
(SSREs) that include an NF-B-responsive GAGACC promoter
sequence305 in the 5 upstream region. However, the induction of TGF- and MCP-1 appear to occur through alternative sites, eg, a TRE/AP-1-responsive element.306 Levels of
transcription factors NF-B and AP-1 are increased in sheared
EC.307 How shear-related transcription factors affect
immediate and persistent gene transcription and how this inductive
pathway differs from other injury-related responses remain to be
elucidated.
Homocysteine.
Homocysteine is a sulfhydryl amino acid formed during the conversion of
methionine to cysteine. Elevated plasma levels of homocysteine may
result from deficiencies of cystathionine--synthase, deficiencies of
enzymes involved in the folate-dependent pathway of homocysteine
remethylation, or deficiencies of folate or vitamin B12 themselves (see
Guba et al308 and Rees and Rodgers309 for reviews). Homozygous deficiency of cystathionine -synthase leads to
markedly elevated plasma concentrations of homocysteine and is
associated with premature atherosclerosis and arterial thrombosis. The
results of several recent large prospective and case-controlled studies
suggest that even modestly elevated levels of homocysteine may pose a
risk factor for atherosclerosis as well as for arterial and venous
thrombosis (reviewed in Mayer et al310), although it is not
clear that all pathways leading to hyperhomocysteinemia pose comparable
risks. Several large prospective studies are underway to assess the
magnitude of this risk.
These observations have led to the identification of several pathways
by which homocysteine may affect the anticoagulant and procoagulant
functions of cultured ECs (Table 2).311 It is important to
consider that most studies to date have used cultured cells exposed for
brief periods to concentrations of homocysteine that exceed that which
is observed in vivo. Clearly, such concentrations of homocysteine
induce formation of hydrogen peroxide312 and oxidized
LDL313 and may be directly cytotoxic for ECs; NO is at
least partially protective.314 However, induction of
TF,315 activation of factor V,316 decreased
binding of t-PA to annexin-II,317 inhibition of
thrombomodulin,318 and reduced expression of heparan
sulfate319 and possibly PGI2,320
among many other changes, have all been observed in ECs exposed to high
concentrations of homocysteine. Homocysteine is also mitogenic for rat
aortic smooth muscle cells.321 That similar effects may
occur in vivo is suggested by vascular dysfunction in monkeys with
diet-induced hyperhomocysteinemia322 and elevated levels of
thrombomodulin and vWF in the plasma of homocysteinemic patients with
peripheral arterial disease. Therapy with pyridoxine and folic acid led
to rapid reductions in the levels of both markers.323
Studies in animal models in which moderately elevated levels of
homocysteine is sustained may provide additional insight into the role
of the endothelium and other pathogenic mechanisms of thrombosis and
atherosclerosis.
Consequences of EC injury on endothelial-derived vasoactive factors.
Healthy human epicardial coronary arteries dilate when acetylcholine is
infused,324 whereas atherosclerotic arteries
constrict325 due to impaired release of NO (see
"Vasoregulation" above) and PGI2 from the
endothelium.326 Loss of vasodilitation in the absence of
overt stenosis has been observed in patients with
hypercholesterolemia,327 increased Lp(a),328
diabetes,329 homocystinuria,330 and possibly hypertension (reviewed in Woodman331 and Heistad et
al332). Similar effects have been observed with advancing
age,333 exposure to cigarette smoke,330,334 and
sedentary life style.335 Endothelial dysfunction is almost
universal 12 to 24 months after cardiac transplantation.336
Indeed, abnormal vasodilator function may be a more sensitive marker of
coronary artery disease in some settings than is
angiography.337
The reduction in NO is attributable in part to lowered levels of eNOS
in atherosclerotic vessels,338 but the reason for this is
uncertain. One clue may be that impaired vasodilatation is especially
marked at coronary branch points where flow and shear stress have been
shown to stimulate NO production in healthy vessels.301 In
addition, free oxygen radicals and hydrogen peroxide generated by EC
exposed to high levels of LDL may inactivate NO.339
Inhibition of NO activity accelerates atherosclerosis in animal
models,340 whereas supplementation with L-arginine, the
precursor of NO, diminishes lesion formation (reviewed in
Cooke341) and reverses endothelial dysfunction in otherwise
healthy young humans with hypercholesterolemia.342 The loss
of NO may impact on multiple steps in the atherogenic
process.341 NO may also counteract the proatherogenic
effects of endothelin (reviewed in Mathew et al343). Oxidized LDL binds to a newly described receptor on ECs344
and increases the production and secretion of ET in cultured ECs and in
intact blood vessels.345 ET is also released by
dysfunctional coronary arteries that constrict in response to
acetylcholine.346 Plasma concentrations of ET are elevated
in asymptomatic patients with hypercholesterolemia and increased plasma
levels of both Lp(a)347 and ET have been reported to
correlate with the severity of atherosclerosis.346
Monitoring the reversal of EC dysfunction.
A significant reduction in cardiac events has been reported as a result
of lipid lowering therapy, but the mechanism responsible for this
benefit has not been elucidated. Little reduction in the
cross-sectional area of preexisting lesions is seen, although progression of the lesions may be slowed348 and incidence
of plaque rupture may be lessened. What is clear is that there is an
improvement in various indirect measures of EC function in vivo
possibly as a result of a more favorable profile of vasoactive agents
that are produced at critical locations.349 Similar
beneficial effects on surrogate markers of EC function have been seen
with the use of antioxidants,350 whereas in other studies
the acute administration of vitamin C has been associated with improved EC-dependent vasodilatation in chronic smokers351 and
patients with coronary artery disease.352 Similar
beneficial effects of angiotensin converting enzyme inhibitors have
been confirmed in some353 but not in all354
animal models (reviewed in Lonn et al355).
Thus, with the advent of potential means to treat atherosclerosis, the
need for reliable, noninvasive surrogate markers of risk and vascular
function have become apparent. Several candidate molecules have
emerged. Abnormalities in serotonin-induced arterial vasodilatation, a
process dependent on NO, precede the development of clinical disease
and resolve within 12 weeks of the institution of cholesterol lowering
therapy.356 Elevated plasma levels of PAI-1 and
thrombomodulin revert towards normal as well.357 In contrast, little change has been seen in the elevated plasma levels of
E-selectin, VCAM-1, and ICAM-1.358 There is also interest in measuring levels of 8-epi PGF2
, an isoprostane with
potent vasoconstrictor activity in the pulmonary and renal circulations generated through free radical catalyzed peroxidation of arachidonic acid by ECs and other vascular cells. Levels of 8-epi
PGF2 in the urine have been used as a marker of oxidant
stress in vivo (reviewed in Morrow and Roberts359). Levels
in smokers are elevated and fall with cessation of smoking or treatment
with vitamin C but not with vitamin E or aspirin
therapy.360
Perspective.
Healthy ECs contribute to the prevention of atherosclerosis in medium
to large arteries by inhibiting platelet activation, limiting the entry
of cells and lipids into the vessel wall, maintaining a
nonproliferative and biochemically quiescent intima,361 and secreting products under appropriate stimuli that limit potentially injurious responses that occur as a byproduct of host response to
injury. These self-protective mechanisms are impaired as a result of
oxidant, chemical, and shear stress, while at the same time the
biochemical profile of the endothelium changes in a way that promotes
inflammatory and fibroproliferative responses. The role of ECs in
preventing or limiting the effects of plaque rupture and terminal
thrombosis is little understood. The injurious processes that initiate
atherosclerosis appear to persist throughout life in most individuals.
Studies are now being conducted to determine the extent to which the
biochemical and functional changes in the vessel wall can be reversed
at different stages of the disease.
Endothelial perturbation and vascular dysfunction in diabetes.
Vascular dysfunction is a contributing factor in the etiology of
several clinically important secondary complications of diabetes mellitus including retinopathy, accelerated atherosclerosis,
microvascular disease, nephropathy, neuropathy, and impaired wound
healing.362,363 The effects of hyperglycemia on EC function
can be imparted through several pathways: (1) production of reactive
oxygen intermediates; (2) direct activation of protein kinase C; (3)
activation of the aldose reductase pathway resulting in an accumulation
of sorbitol and diminished levels of myo-inositol; and (4) nonenyzmatic
glycoxidation of long-lived macromolecules.362,363 Because
glycoxidation of proteins and lipids occurs ubiquitously in patients
with diabetes and is irreversible, its consequences are especially
relevant to long-term vascular dysfunction. Initially, exposure of free amino groups to reducing sugars, such as glucose, results in the formation of early glycation products, Schiff bases, and Amadori products. These are reversibly modified species, such as hemoglobin A1c, used for long-term monitoring of blood sugar in diabetic patients.
Further molecular rearrangements occur, in part due to oxidation,
resulting in irreversible AGEs (Fig 6). The
latter have pathophysiologic relevance in that AGE-modified proteins may not function normally and/or may perturb cellular
properties in a manner distinct from that of the native molecule. This
occurs when the AGE form of the molecule binds to cellular receptors which recognize AGEs, including RAGE364,365 and the
macrophage scavenger receptor.366 RAGE is expressed by
endothelium, monocytes, and smooth muscle cells and is likely to play a
major role in the development of vascular disease in
diabetics.365
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| Fig 6.
A two-hit model of vascular perturbation. Stage 1 shows
the interaction between AGEs, modified biochemical species and their receptors (RAGEs), transmembrane protein receptors of the Ig family present at low levels on a range of cells including ECs in addition to
macrophages (Mfs), smooth muscle cells, and neurons. AGEs may perturb
the normal physiologic function of the modified species and thus alter
the EC's normal vascular functions. Stage 2 details subsequent
perturbations resulting from the superimposed stimuli of accumulated
lipoprotiens as seen in atherosclerotic lesions, foreign materials that
may be seen in wound repair, and bacterial infection that may be seen
in periodontal disease.
|
|
RAGE is a member of the Ig superfamily of cell surface molecules. It is
composed of an extracellular domain with one V-type, followed by two
C-type regions.364,365 There is a single transmembrane spanning domain and a short, highly charged cytosolic tail that likely
transmits the signal of ligand occupancy by interacting cytosolic
transduction molecules. The single RAGE gene is located on chromosome 6 in the major histocompatibility complex between genes for class II and
class III molecules. This proximity of RAGE to genes contributing to
the host response is in keeping with expression of the receptor. In
mature animals, RAGE is present at low levels in a range of cells
(endothelium, smooth muscle cells, mononuclear phagocytes, and
neurons), but after perturbation, as in diabetes, immune/inflammatory
disorders, or Alzheimer's disease, RAGE expression is dramatically
upregulated. In diabetes, AGE-modified proteins appear to act as
ligands for RAGE modulating a number of secondary messenger pathways.
For example, AGE interaction with RAGE results in cellular oxidant
stress eventuating in activation of p21ras, MAP kinases (erk's 1 and
2), and the transcription factor NF-B.367 Such
activation of NF-B results from binding of p50/p65 heterodimers to
DNA binding motifs, as in the gene for vascular cell adhesion
molecule-1 (VCAM-1). RAGE-dependent enhanced VCAM-1 expression is
observed both in cultured ECs and in vivo in mice infused with
AGEs.368 Increased VCAM-1 levels are also observed in
diabetic vasculature upon immunohistological analysis. In parallel with
expression of VCAM-1 on the cell surface, ECs release a soluble form of
VCAM-1 (sVCAM-1) into culture supernatants, potentially providing a
means of monitoring cellular stress in vivo. Patients with diabetes and
microalbuminuria, the latter considered a harbinger of impending future
vascular complications, display higher plasma sVCAM-1 than
those without microalbuminuria.369
AGE-RAGE interaction likely underlies vascular hyperpermeability,
another salient feature of diabetic vasculopathy. Such
hyperpermeability is blocked by anti-RAGE IgG or by preventing AGE
binding by infusion of a soluble form of the extracellular domain of
RAGE (the latter is termed sRAGE). Vascular leakage of solutes in
diabetic animals can be largely blocked by infusion of sRAGE. These
data identify a reversible component of diabetic vascular dysfunction
and suggest that AGE-RAGE-induced cellular perturbation may be a
contributor. The principal insights to be gained from analysis of RAGE
binding to nonenzymatically glycated ligands is probably in the setting of chronic vascular perturbation.365 Because AGE
modification of proteins is irreversible, AGEs accumulated in the
vessel wall are present for extended periods of time. Thus, the
diabetic vascular milieu has properties that distinguish it from that
in euglycemic subjects. A two-hit model can be envisioned (Fig
6) in which tissue and blood AGEs interacting with RAGE
provide a baseline state of vascular activation for the first-hit. The
second stage comprises a superimposed stimulus, such as accumulated
lipoproteins in atherosclerotic lesions, foreign material in wounds,
and bacterial infection in periodontal disease. AGE-RAGE interaction
provides a backdrop of chronic inflammation, with increased expression
of proinflammatory cytokines, thrombogenic factors, cell adherence
molecules, and vascular permeability, which aggravates and probably
accelerates the development of vascular lesions.
Antibody-mediated EC injury: Solid organ transplantation.
Transplantation of vascularized organs, such as kidney, heart, lung,
and liver, has become the treatment of choice for end-stage organ
failure. The key limitations on clinical transplantation today are
rejection of allografts posttransplantation and the shortage of
available donor organs. The EC lining of graft vessels plays a
prominent role in both of these clinical problems.
Despite the enormous advances in clinical immunosuppression of
transplant recipients that have been made in the last 50 years of
practice, the principal cause of graft failure is still rejection, ie,
immunological reactions of the host against graft cell alloantigens that injure and destroy the graft. ECs play three crucial roles in the
process of graft rejection: (1) ECs stimulate the host immune system by
presenting alloantigens in an immunogenic form to host lymphocytes,
thereby helping to initiate graft rejection; (2) ECs respond to host
stimuli, eg, inflammatory cytokines, to promote intragraft inflammation
and thrombosis that contribute to graft injury; and (3) ECs lining
graft vessels are primary cellular targets of the host antigraft
response. In addition, graft ECs are sensors and mediators of
antigen-independent injury to which the graft is subjected during
harvest, transport, and implantation, a dramatic instance of ischemia
reperfusion. The mechanisms by which ECs present antigens to
lymphocytes, promote inflammation in response to cytokines, are injured
by the immune response, and respond to oxidant injury have been
discussed in previous sections of this review and will not be
duplicated in this section. We will focus here on specific issues
related to immunologic allograft rejection.
Rejection reactions are commonly classified according to the time when
they occur after surgical transplantation and by their histopathologic
features.370 Hyperacute rejection occurs within minutes to
hours of perfusion of the graft by host blood, ie, in the perioperative
period. It is characterized by extensive intravascular thrombosis of
graft vessels and consequent graft ischemic infarction. Hyperacute
rejection is mediated by host antigraft antibodies, usually IgM
antibodies reactive with graft endothelial carbohydrate epitopes such
as ABO blood groups, and by complement activation that is initiated by
the antibodies bound to graft ECs. Thrombosis results from EC lysis and
desquamation, exposing thrombogenic subendothelial basement membrane,
or, in cases of sublytic quantities of complement depositon, by loss of
endothelial antithrombotic mechanisms (eg, shedding of cell surface
anticoagulant heparan sulfate) combined with activation of endothelial
prothrombotic mechanisms (eg, release of stored high molecular weight
vWF, release of lipid procoagulants, and possibly induction of
TF).371 Matching of donors and recipients for ABO blood
groups has significantly reduced the incidence of hyperacute rejection
in allografts.
Acute rejection reactions usually develop between the first and second
week after transplantation. Although a variety of effector mechanisms
may be involved, recent studies of human allograft biopsies have
emphasized the primary role of cytolytic cells, principally
CTLs.372,373 Some host CTLs recovered from rejecting grafts
have shown specificity for graft ECs over graft
leukocytes.374 Because the specificity of CTL is determined
by the antigens involved in their induction (ie, the same antigen
receptor mediates initial differentiation and subsequent effector
function of CTL), graft ECs must have played a role in stimulating host
CTL development by presenting antigen to precursor cells, ie, to
resting CD8+ T cells recruited from the circulation into
the graft. Lysis of microvascular ECs is a prominent and early
component of acute cell-mediated rejection.375 More severe
rejection reactions typically involve injury of larger graft vessels as
well. Such vascular rejection is believed to start as a host CTL
reaction against graft arterial or arteriolar ECs (called
endothelialitis or intimal arteritis at this early
stage373) and may progress to severe necrotizing,
transmural vasculitis. The most severe vascular rejection reactions
appear to involve host antigraft antibodies (both IgG and IgM) as well
as cytolytic lymphocytes. Presensitized hosts (eg, resulting from a
prior transplantaton procedure) who have expanded numbers of memory T
or B cells reactive with the donor may show accelerated acute rejection
during the first few days after transplantation370). These
accelerated rejection reactions are similar to experimental second set
rejection seen in animal models of retransplantation. The use of tissue
typing (for renal transplantation) and of improved immunosupression
(especially since the introduction of cyclosporin A) have reduced the
incidence of graft loss due to acute and/or accelerated
rejection to fewer than 10% of organs. ECs are considered prime
targets for further improvements in immunosupression, eg, by targeting
adhesion molecules such as ICAM-1 to reduce posttransplant
ischemia-reperfusion, inflammation, and CTL effector functions.
With current advances in controlling acute rejection, the major cause
of graft loss has become chronic rejection.376 Chronic rejection appears in biopsies as replacement fibrosis of graft parenchyma, developing over months to years. These changes are widely
thought, at least in cardiac and renal transplantation, to be secondary
to graft ischemia caused by progressive occlusion of the lumen of graft
arteries (called graft arteriosclerosis). Graft arteriosclerosis is
characterized by concentric, diffuse intimal hyperplasia of large,
medium, and small graft arteries. These changes are accelerated
compared with atherosclerosis in that they can develop into clinically
significant lesions as early as 6 months to a few years
posttransplantation. Despite all of the advances in immunosuppresion
for acute rejection, the incidence of allograft failure to chronic
rejection has remained at about 10% of grafts per year, with no
evidence of improvement.
Graft arteriosclerosis is restricted to graft vessels, ie, it
completely spares the host's vessels. Involved graft arteries contain
increased numbers of intimal smooth muscle cells and deposition of
extracellular matrix accompanied (or preceeded) by a sparse subendothelial infiltrate of host T cells and
macrophages.377 Cytolytic effector cells are markedly fewer
than in acute vascular rejection,378 and the endothelium
shows only rare apoptotic cells.379 The major theories of
pathogenesis are that graft arteriosclerosis results from chronic,
low-level endothelial injury (ie, persistent endothelialitis caused by
CTLs and/or alloantibodies), followed by fibroproliferative
repair, or that graft arteriosclerosis results from a conversion of an
acute cytolytic immune response to a chronic delayed-type
hypersensitivity reaction in response to persistent immune stimulation
by graft ECs. There is currently no therapy for graft arteriosclerosis
except retransplantation. Future therapy may be targeted at preventing
the intimal smooth muscle fibroplastic reaction rather than further
increases in immunosuppression.
The next horizon in transplantation is to address the donor organ
shortage by xenotransplantation of animal organs (eg, pigs) into human
recipients.380 The use of pig organs has raised concerns about introducing new infectious agents into the human population, but
the major practical problem is a very high incidence of hyperacute rejection. Two factors contribute to development of severe,
uncontrollable hyperacute rejection of pig xenografts by human or old
world monkey recipients. First, all mammals, except humans and old
world monkeys, express a galactose -1,3 galactose carbohydrate
epitope instead of ABO blood groups on their ECs.381
Moreover, virtually all humans have high levels of circulating natural
IgM antibodies reactive with this alternative epitope, so that ABO
matching cannot be used to evade hyperacute rejection in
xenotransplantation. Second, the problem of abundant natural antibody
is compounded by the fact that pig ECs express complement regulatory
proteins, eg, DAF and CD59, that are unable to control the human
complement system, ie, they are species specific for pig complement
proteins.382 The combination of high levels of
complement-activating IgM antibodies and limited EC resistance to human
(or primates) complement proteins invariably leads to rapid and
overwhelming intravascular graft thrombosis.
A major current effort is underway to produce transgenic pigs that will
have reduced levels of galactose -1,3 galactose and/or express human complement regulatory proteins. If successful,
transplanters will still need to address later phases of the
human-antipig rejection reaction (eg, potentially strong acute cellular
rejection due to expression B7.2 costimulator molecules on pig
ECs383 or to strong NK reactions384 due to
possibly antibody binding and absence of self class I MHC molecules on
pig ECs). Some of these problems may be partly
ameliorated by the failure of pigs to respond to certain human
cytokines (eg, to IFN-385), but additional studies will
be needed to determine the significance of these differences.
Systemic lupus erythematosus (SLE) and the antiphospholipid antibody
syndrome (aPS).
Immune-mediated endothelial dysfunction may contribute to the
development of thrombosis in patients with SLE and the aPS (see McCrae
and Cines386 for review). One mechanism by which
endothelial damage and/or activation may occur is through the
effects of EC-reactive antibodies. Several groups have demonstrated
anti-EC antibodies (AECA) in sera of patients with SLE387
and in patients with primary and secondary aPS (see McCrae et al,388 among others). Controversy remains as to whether
antiphospholipid antibodies per se comprise the biologically important
subpopulation of AECA (see Cines389 for review), although
recent studies suggest that they may activate ECs through an effect on
the plasma protein 2-glycoprotein I.390 AECA
have been shown to alter the anticoagulant and procoagulant activities
of cultured ECs in a number of ways. However, the in vivo importance of
these antibodies in the pathogenesis of thrombosis remains unknown.
Indeed, in only some studies has the presence of AECA correlated with
thrombotic events or disease activity.388 Nevertheless, the
fact that such antibodies induce the secretion of markers of EC
injury/activation such as vWF from cultured ECs,388 when
considered in light of reports demonstrating elevated levels of vWF in
the plasma of patients with SLE,391 suggests that at least
some of these in vitro effects may reflect processes that occur in
vivo.
Heparin-induced thrombocytopenia and thrombosis (HITT).
Approximately 1% to 3% of patients who receive heparin develop severe
thrombocytopenia, approximately 20% of whom also develop venous
and/or arterial thrombi (see Arepally and Cines392
and McCrae and Cines393 for reviews). Plasma from
approximately 90% of patients with HITT contain antibodies that bind
to complexes of heparin and platelet factor 4 (PF4).394 PF4
released from activated platelets may form complexes with heparin on
the surface of activated platelets, targeting them for
Fc
RIIA-dependent activation by
antiheparin-PF4 antibodies. However, the remarkable propensity of
patients with HITT to develop thrombosis may also be promoted by the
capacity of these antibodies to recognize PF4 bound to EC-heparan
sulfate proteoglycans, which stimulate ECs to express TF and to bind
platelets.395,396
EC-reactive antibodies in other vasculitic disorders.
AECAs have been described in several other disorders in which their
role in pathogenesis is even less certain. PR-3, a common target of
antineutrophil cytoplasmic antibodies (ANCA) is expressed on activated
ECs in vitro397 and has been implicated in vascular injury
in an animal model of vasculitis.398 However, EC-specific antibodies, apparently distinct from ANCA, have also been described in
many patients with Wegener's granulomatosis.399 Plasma
from children with the hemolytic uremic syndrome contain lytic AECA that recognize an unidentified EC surface protein that is suppressed by
IFN- in vitro.400 AECA have also been implicated in
mixed connective tissue disease, rheumatoid arthritis, and
scleroderma,401 in which EC apoptosis has been
implicated,402 as well as in
atherosclerosis,403 Kawaski's disease,404
Bechet's disease,405 and various forms of
vasculitis.406 In each of these conditions, elevated levels of EC-derived proteins have also been described in the plasma of
affected patients implying endothelial activation or
injury.407 However, a pathogenic role of AECA or immune
complexes in human vasculitis has not been proven. It is also pertinent
to note that complex changes in antigen expression occur when ECs have
been activated by cytokines or other agonists in vitro (see
Favaloro408 for review) and in vivo.409 This
activation promotes cell mediated immunity, promotes leukocyte/platelet
adhesion (see "EC Pertubation and Vascular Disease" above) and
exposes cryptic autoantigens. Fc receptors
capable of binding circulating immune complexes may
exist410 or can be induced on ECs411 at certain
vascular sites.
Complement-mediated EC activation.
The vascular endothelium is exposed to activated complement components
as a consequence of antigen-antibody interactions that occur naturally
in plasma and within the vessel wall in certain pathologic
conditions.387 ECs also constitutively express several complement proteins412 and can be induced to synthesize
others by various cytokines,413 at least in vitro.
Complement deposition on the vasculature is controlled, in part, by
concerted actions of the regulatory proteins C1-esterase inhibitor,
which is secreted by ECs,414 and by decay-accelerating
factor, membrane cofactor protein of complement, and homologous
restriction factor, which are expressed on the cell
surface.415-419 Complement that deposits on the endothelium
when these containment mechanisms are exceeded can increase vascular
permeability, stimulate procoagulant pathways, and recruit ECs to
become active participants in the inflammatory processes.
For example, multiple components of the complement cascade act in
concert to augment the recruitment of leukocytes to sites of vascular
inflammation. Binding of C1q to specific EC receptors420 augments expression of E-selectin and possibly ICAM-1 and
VCAM-1,421 C5a upregulates the expression of
P-selectin,422 and the terminal C5b-9 membrane attack
complex (MAC) acts synergistically with TNF- to stimulate expression
of E-selectin and ICAM-1.423 Sublytic concentrations of MAC
also activate the NF-B pathway leading to secretion of IL-8 and
MCP-1.424
MAC also stimulates cultured ECs to express TF,425,426 to
release large vWF multimers,427 and to release procoagulant
microvesicles containing anionic phospholipids and binding sites for
factor Va that accelerate prothrombinase activity.428 On
the other hand, MAC also stimulates production of
PGI2429 and the complement components C7 and C9
provide sites for the binding and activation of
plasminogen.430 However, as with other areas of research in
vascular biology, studies have been confined largely to cultured cells
and additional studies are required to elucidate the relative
contribution of complement-dependent responses in vivo.
Thrombotic disorders of uncertain cause: Thrombotic thrombocytopenic
purpura (TTP) and the hemolytic uremic syndrome (HUS).
TTP and HUS are related-disorders characterized pathologically by the
development of platelet microthrombi that occlude small arterioles and
capillaries and clinically by microangiopathic hemolytic anemia and
thrombocytopenia. Endothelial dysfunction plays a prominent
role in the pathogenesis of both disorders (see Moake431
and Heild432). Approximately 90% of cases of HUS occur in
early childhood, often after an episode of bloody diarrhea caused by
enteropathic strains of Escherichia coli that release an
exotoxin, designated verotoxin-1 (VT-1), which is similar to the 70-kD
Shiga toxin 18. VT-1 binds with high affinity to globotriosylceramide (Gb3) receptors expressed at the highest density on renal glomerular ECs.431 VT-1 is directly cytotoxic to ECs. In addition,
VT-1 promotes neutrophil-mediated EC injury433,434 and
induces the production of TNF- by monocytes435 and cells
within the kidney.436 In turn, TNF-, in concert with
IL-1, increases Gb3 expression and exacerbates the sensitivity of the
endothelium to toxin-mediated437 and
antibody-mediated404 cytotoxicity, promotes vWF
release,438 and impairs fibrinolytic
activity.44 In accord with this putative pathogenic
mechanism, elevated plasma levels of PAI-1 have been reported to be a
sign of a poor prognosis in childhood HUS.439 EC injury may
also contribute to the pathogenesis of the microangiopathic syndromes
that may follow the use of certain chemotherapeutic agents,440 cyclosporin,441 quinine/quinidine
(see Gottschall et al442 for review), or after bone
transplantation.440
There is considerable evidence to suggest that EC injury plays a role
in the pathogenesis of TTP. The most exhaustively studied protein in
this regard is plasma vWF, which circulates in plasma as oligomers that
range in size from 1 to 15 × 106 kD. The so-called
unusually large vWF multimers (ULvWF) are normally found in
subendothelial matrix, in the supernatant of cultured ECs,431 and in platelet releasates, but are not normally
detected in plasma.431 Platelet microthrombi in TTP contain
abundant vWF but little fibrinogen, in contrast to those seen in DIC. A
subgroup of patients has been identified who suffer from chronic,
relapsing TTP and whose plasma continues to contain elevated levels of
ULvWF between relapses.443 Furthermore, plasma from
patients with sporadic or isolated episodes of TTP often contains
either ULvWF or decreased amounts of larger vWF multimers during
periods of active disease. ULvWFs may exacerbate microvascular
thrombosis through their ability to aggregate platelets at high levels
of shear stress. The secretion of ULvWF by cultured ECs is stimulated
by many agonists including Shiga toxin.431 However,
elevated levels of vWF occur in other thrombotic microangiopathies, and
their exact role in TTP/HUS requires further study. Reports of elevated
levels of thrombomodulin,444 tissue-type plasminogen
activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1),445 ELAM-1,446 and decreased levels of
PGI2447 and TFPI448 in plasma from
patients with TTP provides additional support for the notion that
endothelial damage plays a pivotal role in the pathogenesis of the
disease.
The events that initiate TTP remain unknown. AECA have been described
in TTP and HUS, but their role is uncertain. More recently, plasma from
patients with TTP and HUS has been reported to induce apoptosis in
microvascular ECs; it is of great interest that cells from dermal,
renal, and cerebral origin were most susceptible, whereas pulmonary and
coronary arterial cells were not.46 The plasma factors
responsible for these changes remain to be identified.
Pregnancy-induced hypertension.
Pregnancy-induced hypertension (or preeclampsia) is the most common
medical disorder of pregnancy, affecting 5% to 13% of all primaras.
Although the clinical manifestations of preeclampsia are generally not
evident until the third trimester, the pathogenesis of this disorder
may involve a deficiency in placentation,449 the process in
which fetal trophoblast cells remodel the maternal uterine spiral
arteries early in pregnancy. Incomplete remodeling of the spiral
arteries leads to compromised placental perfusion. Alterations in EC
morphology occur within the placenta450 and in the
glomerular capillaries (glomerular
endotheliosis), the latter being
characterized by EC swelling and lipid accumulation (see
Ferris451 for review). Fibrin deposition in
microvasculature is common. Affected women show increased
responsiveness to the pressor effects of angiotensin II,314
increased amounts of thromboxane A2 relative to
PGI2 in their urine,452 elevated plasma levels of endothelin,453 and their umbilical vessels demonstrate
less PGI2 synthesis and decreased NO release in response to
bradykinin (see Ferris451 for review). Additional evidence
suggesting endothelial damage is the reported findings of elevated
plasma levels of EC-derived fibronectin,454,455
vWF,455 and PAI-1455 in affected women. Importantly, increased levels of vWF456 and cellular
fibronectin454 may be detected before the onset of clinical
manifestations.
The pathophysiology of EC damage in preeclampsia remains a mystery.
Some,457,458 but not all groups,459,460 have
reported that plasma from affected women is cytotoxic for cultured ECs. Preeclamptic sera have also been reported to impair EC
proliferation,461 stimulate fibronectin
release,462 increase triglyceride
accumulation,463 and increase PDGF
synthesis464; variable effects on PGI2
synthesis have been reported.463,465 A role for
abnormalities of lipid peroxidation,466 for immunologic factors, and for underlying, but otherwise inapparent, maternal vascular disease (see Ness and Roberts467 for review) have
also been advanced. Yet, it must be noted that all of these studies remain largely unconfirmed, the putative injurious plasma factor(s) has
yet to be identified, and the pathophysiology and significance of EC
injury outside of the terminal cases of eclampsia remains enigmatic.
| |
CONCLUSION |
The endothelium can no longer be viewed as a static physical barrier
that simply separates blood from tissue. Rather, it is now clear that
the endothelium helps to coordinate functions of differentiated tissues
in a way that meets the requirements of the organism as a whole. In
part, this is accomplished by the location of the endothelium at the
interface with the blood and the capacity of these specialized cells to
receive and transmit biochemical and physical information
bidirectionally. Information sensed on the lumenal surface of the
endothelium can be transmitted either by direct permeation or active
transport of soluble mediators through the capillaries to deeper
tissues or indirectly through the capacity of ECs to modulate the
behavior of smooth muscle cells and other components of the vessel
wall. In turn, physiologic and pathophysiologic events in tissue alter
EC interactions with soluble and cellular blood components.
The endothelium, as with all cell types, displays an immediate and
prototypic response to diverse agonists that is modulated in complex
ways by subsequent events. In the case of the endothelium, this first
response appears designed to prevent physical disruption of the vessel
wall by trauma, microbial organisms, toxins, or other threats to the
maintenance of intravascular volume and oxygen delivery. This
protective response is accomplished by the rapid transformation of the
endothelium to a procoagulant, vasoconstrictive, and proinflammatory
state that has multiple effects on of its structure and behavior.
Several ramifications of this reflexive, adaptive response of the
endothelium have now become evident. First, it is clear that ECs
rapidly undergo some of these same biochemical and phenotypic changes
soon after being placed in culture, as a consequence of which the
behavior of the unperturbed endothelium cannot be reliable inferred
from currently available in vitro techniques.
Second, an extensive experimental literature has emerged supporting the
notion that several common human vascular diseases are in part a
consequence of the same responses of the endothelium to stress; ie,
that prolonged or exaggerated endothelial activation leads to
dysfunction that is an early, often preclinical component of vascular
disease. Unfortunately, it is generally impossible to access vascular
tissue directly and sequentially during these preclinical stages of
disease development; without such tissue, the EC contribution to
disease development can only be inferred. As a consequence, most
research in vascular biology continues to (1) focus on the footprints
of disease by analyzing damaged vessels, generally at the endstage of
the process; (2) link putative circulatory factors to disorders through
their effect on cultured ECs, often derived from unaffected tissue; and
(3) develop animal models that may simulate human diseases.
Third, it is now clear that the endothelium is not a homogeneous organ.
ECs from different vascular beds show highly differentiated functions
as a consequence of genetic diversity and the impact of specialized
surroundings. These biochemical and phenotypic differences extend to
their susceptibility to injury and effect function of the vasculature
as a whole.
Fourth, there is remarkably little information on the potential
contribution of genetic differences in EC behavior among individuals with respect to bleeding disorders, thrombosis, atherosclerosis, and
vasculitis. Without such information, our current approach to studying
these major vascular disorders can be compared with the study of anemia
without appreciating the existence of hemoglobinopathies or the study
of bleeding disorders without appreciating the contribution of genetic
abnormalities in platelet function. It is hoped that future research
will enable the direct study of EC behavior and thereby enhance our
understanding of the contribution of the endothelium to vascular
biology.
View larger version (119K):
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| Fig 7.
EC injury in a case of antiphospholipid antibody syndrome
(photographs courtesy of Emma E. Furth, MD, Department of Pathology and
Laboratory Medicine, University of Pennsylvania, Philadelphia, PA). EC injury seen in a duodenal biopsy from a
40-year-old woman who presented with profuse intestinal bleeding and
was found to have a lupus anticoagulant and a markedly positive
anticardiolipin antibody. (A) Elastic stain (original magnification × 200) highlighting a fresh thrombus (right) with the beginning stages of
organization and EC ingrowth, an older organized thrombus with
fibroblast proliferation (center), within a vessel showing vacuolated,
injured, and disrupted ECs. (B) A trichrome stain (original
magnification × 400) of the same field highlighting the thrombus
material (red acellular material on the right) with early stages of
organization. (C) A hematoxylin and eosin (H and E) stain (original
magnification × 400) showing fibrinoid intimal necrosis (right) in
the absence of an inflammatory reaction within a small vessel in the
same duodenal biopsy as shown in (A) and (B). The ECs show marked
vacuolization (left). The surrounding eosinophilic vascular cells are
smooth muscle cells surrounded by fibroblasts. (D) A higher power view
(original magnification × 600) of the same biopsy showing four
capillaries with grossly vacuolated ECs and luminal effacement.
|
|
| |
FOOTNOTES |
Submitted August 13, 1997;
accepted February 16, 1998.
Address reprint requests to Douglas B. Cines, MD, Department of
Pathology and Laboratory Medicine, University of Pennsylvania, 513A
Stellar-Chance, 422 Curie Blvd, Philadelphia, PA 19104; e-mail: dcines{at}mail.med.upenn.edu.
| |
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