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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 577-580
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Plasminogen activator inhibitor-1 and vitronectin promote
vascular thrombosis in mice
Daniel T. Eitzman,
Randal J. Westrick,
Elizabeth
G. Nabel, and
David Ginsburg
From the Cardiovascular Research Center and Division of Molecular
Medicine and Human Genetics, Department of Internal Medicine, and the
Howard Hughes Medical Institute, University of Michigan Medical Center,
Ann Arbor, MI.
 |
Abstract |
Occlusive thrombosis depends on the net balance between platelets,
coagulation, and fibrinolytic factors. Epidemiologic information suggests that plasminogen activator inhibitor-1 (PAI-1), a central regulator of the fibrinolytic system, plays an important role in
determining the overall risk for clinically significant vascular thrombosis. Vitronectin (VN), an abundant plasma and matrix
glycoprotein, binds PAI-1 and stabilizes its active conformation. This
study assessed the role of PAI-1 and VN expression in the formation of
occlusive vascular thrombosis following arterial or venous injury. The
common carotid arteries of 17 wild-type (WT) mice and 8 mice deficient
in PAI-1 were injured photochemically while blood flow was continuously
monitored. WT mice developed occlusive thrombi at 52.0 ± 3.8 minutes
(mean ± SEM) following injury; mice deficient in PAI-1 developed
occlusive thrombosis at 127 ± 15 minutes
(P < .0001). Mice deficient in VN (n = 12)
developed vascular occlusion 77 ± 11 minutes after injury,
intermediate between the values observed for WT mice
(P < .03) and mice deficient in PAI-1 (P < .01). PAI-1 and VN also affected the time to occlusion
after injury to the jugular vein. Three WT mice developed
occlusive venous thrombosis an average of 39.7 ± 1 minutes following
the onset of injury, whereas the jugular veins of 4 mice deficient in
PAI-1 and 4 deficient in VN occluded 56.7 ± 5 and 58.7 ± 2 minutes,
respectively, following injury (P < .04 and
P < .01 compared to WT mice). These results suggest that
endogenous fibrinolysis and its regulation by PAI-1 and VN have
important roles in the development of occlusive vascular thrombosis
after vascular injury.
(Blood. 2000;95:577-580)
© 2000 by The American Society of Hematology.
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Introduction |
Vascular thrombosis after injury is the critical event
leading to acute vascular syndromes including myocardial infarction, unstable angina pectoris, and stroke.1 The fate of a
forming thrombus is determined by the balance between coagulation
factors and platelets favoring occlusive clot formation and the
fibrinolytic system favoring clot dissolution. The relative
contributions of the individual factors involved in occlusive thrombus
formation following vascular injury are poorly understood.
Intravascular fibrinolysis is mediated primarily by the fibrinolytic
protease, plasmin, which is derived from its inactive precursor
plasminogen through the action of the plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA).2 Plasminogen activator inhibitor-1 (PAI-1) is a member of the SERPIN gene family and regulates the plasminogen activation system by forming irreversible inhibitory complexes with uPA
and tPA.3 Vitronectin (VN), an abundant plasma and matrix
glycoprotein, binds PAI-1 and may regulate its activity by stabilizing
the active PAI-1 conformation4 as well as potentially regulating PAI-1 clearance.5 In addition, VN may play an
important role in cellular migration.6 States of PAI-1
deficiency in humans are associated with abnormal bleeding, indicating
an important role of PAI-1 in stabilization of the hemostatic
clot.7-9 In contrast, inhibition of endogenous fibrinolysis
by elevated plasma PAI-1 levels may constitute an important risk factor
for myocardial infarction10 and deep venous
thrombosis.11
Genetically engineered mice carrying targeted deletions of genes
encoding fibrinolytic system components have provided a powerful model
for the in vivo characterization of vascular thrombosis.12 Mice deficient in PAI-1 exhibit enhanced fibrinolysis13-15
and animals deficient in VN demonstrate reduced plasma PAI-1 levels following endotoxin administration, consistent with an important role
of VN in ensuring the stability of PAI-1 in vivo.5
Endogenous fibrinolysis and its regulation by PAI-1 and VN may be
important in the development of occlusive vascular thrombosis after
vascular injury. To test this hypothesis we analyzed wild-type (WT)
mice, mice deficient in PAI-1, and mice deficient in VN using a
photochemically induced arterial and venous thrombosis model.
| |
Materials and methods |
Mice
Mice deficient in PAI-1 were a gift of P. Carmeliet and D. Collen.16 Control C57BL/6J mice were purchased from Jackson
Labs, Bar Harbor, ME. Mice deficient in PAI-1 and VN were back-crossed to C57BL/6J mice for at least 8 generations. All mice were maintained on standard chow. Mice were genotyped as previously
described.14 All animal care and experimental procedures
complied with the Principles of Laboratory and Animal Care
established by the National Society for Medical Research and were
approved by the University of Michigan Committee on Use and Care of Animals.
Induction of carotid artery and jugular vein thrombosis
Control C57BL/6, PAI-1-deficient and VN-deficient male mice
(6-8 weeks old) weighing an average of 23 g were anesthetized with 1.3 mg intraperitoneal sodium pentobarbital (Butler, Columbus, OH). Mice
were then secured in the supine position and placed under a dissecting
microscope (Nikon SMZ-2T, Mager Scientific, Inc., Dexter, MI).
Following a midline cervical incision, the right common carotid artery
was isolated and a Doppler flow probe (Model 0.5 VB, Transonic Systems,
Ithaca, NY) was applied. The probe was connected to a flowmeter
(Transonic Model T106) and interpreted with a computerized data
acquisition program (Windaq, DATAQ Instruments, Akron, OH). Rose bengal
(Fisher Scientific, Fair Lawn, NJ) was diluted to 10 mg/mL in
phosphate-buffered saline and then injected into the tail vein in a
volume of 0.12 mL at a concentration of 50 mg/kg (arterial protocol) or
25 mg/kg (venous protocol) using a 27-gauge Precision Glide needle with
a 1-mL latex free syringe (Becton Dickinson and Co., Franklin Lakes, NJ). Just before injection, a 1.5-mW green light laser (540 nm) (Melles
Griot, Carlsbad, CA) was applied to the desired site of injury from a distance of 6 cm for 60 minutes or until
thrombosis occurred. Flow in the vessel was monitored for 150 minutes from the onset of injury, at which time the experiment was
terminated. A similar protocol was used for studies of the right
internal jugular vein.
Histology
To confirm occlusive thrombosis, carotid arterial segments
subjected to injury were excised and embedded in paraffin. Sections were then stained with hematoxylin and eosin.
Statistical analysis
The significance of differences in time to occlusion
between groups was determined using the Student 2-tailed t
test. A P value of < 0.05 was considered significant.
| |
Results |
A murine model for arterial and venous thrombosis
To establish a photochemically induced thrombosis model in
mice, multiple experiments were performed to determine appropriate conditions for reproducible induction of vascular occlusion. The right
common carotid artery and right internal jugular vein were selected
because of their accessibility and ease of monitoring flow. Control
experiments in WT mice revealed that rose bengal at a dose of 50 mg/kg
with the laser light source 6 cm away from the carotid artery injury
site produced reproducible occlusive thrombosis that was confirmed with
hematoxylin and eosin staining of tissue sections. These conditions
also produced jugular venous occlusion when applied to the right
internal jugular vein in control mice with a mean time to occlusion of
26.5 ± 9 minutes (n = 8). However, to increase the sensitivity of
the venous model for detecting changes in fibrinolysis, the dose of
rose bengal was decreased to 25 mg/kg, which resulted in a prolongation
of the time to occlusion to 39.7 ± 1 minutes in WT animals
(n = 3). Visual inspection through a dissecting microscope
consistently revealed an intraluminal plug in the carotid artery or
jugular vein that corresponded with flow cessation.
Effect of PAI-1 or VN deficiency on development of
occlusive arterial thrombosis
To determine if the development of carotid artery occlusion
was affected by the level of PAI-1 expression, mice deficient in PAI-1
and WT mice were subjected to photochemical injury at the mid common
carotid artery. Carotid flow was continuously monitored for 150 minutes. Mice that failed to form occlusive thrombosis during the
observation period were assigned a value of 150 minutes for statistical
analysis. Seventeen WT control mice formed occlusive thrombus at the
site of light application an average of 52 ± 3.8 minutes (mean ± SEM) following rose bengal injection, whereas 8 mice deficient in
PAI-1 developed occlusive thrombosis with a mean time of 127 ± 15 minutes (6 mice failed to occlude during the observation period)
following injury (P < .0001).
Twelve mice completely deficient in VN were also tested in the carotid
thrombosis model. The mean time to occlusion for VN null mice was 77 ± 11 minutes (2 mice failed to occlude during the observation
period), which was longer than WT mice (P < .03) but
shorter than mice deficient in PAI-1 (P < .01) (Figure
1).
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| Fig 1.
Effect of PAI-1 and VN deficiency on arterial thrombosis.
The carotid arteries of WT mice, mice deficient in PAI-1, and mice
deficient in VN were continuously monitored for flow following
photochemical injury to the mid common carotid artery. The average time
to occlusive thrombosis was longer in mice deficient in PAI-1 and in
mice deficient in VN compared with WT mice. The time to clot in
PAI-1-deficient mice was also longer than that of VN-deficient mice.
 , P < .03 compared with VN -/-mice; ,
P < .0001 compared with WT mice; #, P < .01
compared with WT mice.
|
|
Effect of PAI-1 or VN deficiency on development of
occlusive venous thrombosis
To assess the effect of PAI-1 deficiency on the formation of a
venous thrombus, a jugular vein injury model was established. After
injection of rose bengal in a dose of 25 mg/kg, WT mice formed
occlusive thrombosis at an average of 39.7 ± 1 minutes (n = 3).
Compared with WT mice, the time to occlusion was prolonged to 56.7 ± 4 minutes (n = 4, P < .04) in the mice deficient in PAI-1 and to 58.7 ± 2 minutes (n = 4, P < .01) in the
VN-deficient mice (Figure 2). The
difference in the time to clot between mice deficient in PAI-1 and VN
is not statistically significant.
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| Fig 2.
Effect of PAI-1 and VN deficiency on venous thrombosis.
The internal jugular veins of WT, PAI-1-deficient, and VN-deficient
mice were continuously monitored for flow following photochemical
injury to the internal jugular vein. The average time to occlusive
thrombosis was longer in mice deficient in PAI-1 and in mice deficient
in VN compared with WT mice. *P < .04 compared with WT;
**P < .01 compared with WT mice.
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| |
Discussion |
Plasminogen activator inhibitor-1, the primary inhibitor of tPA and
uPA, is a central regulator of the blood fibrinolytic system.3 Epidemiologic studies of myocardial infarction and deep venous thrombosis,10,11 as well as studies from humans deficient in PAI-1,7-9 suggest that plasma levels of PAI-1
contribute to the maintenance of occlusive thrombosis at sites of
vascular injury, although these studies are controversial. Animal
studies have demonstrated enhanced lysis of formed thrombi in the
setting of PAI-1 deficiency.15,17 In a recent report,
deficiency of PAI-1 did not affect the time to thrombosis in the murine
carotid artery following ferric chloride injury, although subsequent
lysis of the thrombus was enhanced.15 In a murine pulmonary
embolism model, lysis of a preformed thrombus was also accelerated in
mice with PAI-1 deficiency16 and administration of an
inhibitory PAI-1 antibody in a canine coronary thrombosis model
resulted in a reduced reperfusion time when administered with
tPA.18 In vitro studies also support the role of PAI-1 as
an important inhibitor for the lysis of platelet-rich clots, because
accelerated lysis is observed when the platelets are derived from a
patient deficient in PAI-119 or in the presence of a PAI-1
inhibitor.20
The present study used a model in which flow is continuously monitored
during arterial injury, enabling the accurate assessment of time to
occlusive thrombus formation. Intravenous rose bengal activated by a
green laser light was used to elicit thrombosis because this method
produces endothelial damage21 and does not require intra-arterial invasion or full thickness injury. In rats and guinea pigs, reproducible occlusive thrombus formation
results.21-23 This method of injury has also been applied
in the mouse femoral artery to elicit formation of
neointima24 and in the mouse carotid artery to cause
thrombosis.25 The subtle endothelial injury induced by rose
bengal as compared to other vascular injury models15,26 may
provide a sensitive measure of altered fibrinolysis. Our observation of
a markedly prolonged time to occlusion in PAI-1 null mice suggests that
simultaneous fibrin formation and fibrinolysis are occurring during
clot formation, with the net balance determining time to occlusion.
During the preparation of this manuscript Matsuno et al.27
independently demonstrated an effect of PAI-1 on time to occlusion
using a similar model of photochemical injury. However, these workers
observed a much shorter baseline time to occlusion, likely due to
the greater intensity of the light source.
The high concentration of VN in plasma and its wide distribution in
subcellular matrices as well as its interactions with PAI-14 and other cell adhesion molecules suggest a complex
role in the formation and stabilization of an occlusive thrombus. Mice
deficient in VN exhibit decreased levels of plasma PAI-1 that should
presumably lead to enhanced fibrinolysis. However, in a ferric
chloride-induced carotid thrombosis model, mice lacking VN exhibited
enhanced thrombus formation compared to WT mice, suggesting that VN may
exert a previously unappreciated anticoagulant function.28
In contrast, the photochemical injury reported here results in a
prolonged time to occlusion in the absence of VN. Taken together, these results suggest that VN may have competing positive and negative effects on thrombus formation with the former predominant in the more
rapid ferric chloride model (17 minutes)28 and the latter the primary determinant in the more subtle rose bengal injury (52 minutes). Of note, ferric chloride applied to the vessel adventitia causes a full thickness (outside-in) injury, whereas the photochemical injury damages the vessel wall from the inside out. Thus, the depth of
vessel wall injury is likely greater with ferric chloride and the
contribution of VN to thrombosis may vary significantly depending on
the severity of vascular injury. In addition, other differences between
the 2 protocols such as depth of anesthesia, the mechanics and timing
of carotid artery isolation, and application of the flow probe may
exert varying effects on thrombosis in these models.
Similar to our observations in the carotid artery, rose bengal-induced
thrombosis in the jugular vein was also delayed in both PAI-1 and VN
null mice. The greater sensitivity of the jugular vein to a lower
dose of rose bengal may be secondary to the thinner vessel wall,
perhaps allowing a more intense light exposure to the endothelium.
Other factors such as hemodynamic differences between the arterial and
venous circulations might also influence the clotting times. The
similar prolongations of venous clotting times in the PAI-1 and VN null
animals, in contrast to the more modest effect of VN deficiency in the
arterial model, could be the result of varying contributions from PAI-1
in endothelial, plasma, platelet, or vascular smooth muscle cell
compartments. For example, the time to clot in the thin-walled vein may
be more dependent on circulating plasma PAI-1 and its stabilization by VN, with the absence of VN reproducing the state of PAI-1 deficiency. In the carotid artery, local release of PAI-1 from medial smooth muscle
cells or other components of the vessel wall, or a greater contribution of platelet PAI-1, may result in less dependence on
stabilization by VN.
Our results indicate that endogenous fibrinolysis and its regulation by
PAI-1 and VN are important in the development of occlusive vascular
arterial and venous thrombosis after vascular injury in mice. These
results also suggest that alterations of endogenous fibrinolytic
balance through modulation of PAI-1 and VN might be a useful
therapeutic target for the prevention of acute vascular thrombosis in humans.
| |
Acknowledgments |
We gratefully acknowledge D. Siemieniak for technical assistance with
the photochemical injury model, J. Tyson for assistance with histology,
and the University of Michigan Center for Statistical Consultation and
Research for statistical assistance.
| |
Footnotes |
Submitted July 14, 1999; accepted September 14, 1999.
Supported by National Institutes of Health grants HL03695-02 and HL57345.
D. Ginsburg is a Howard Hughes Medical Institute Investigator.
Reprints: Daniel T. Eitzman, University of Michigan Medical
Center, MSRB III Room 7301, 1150 Medical Center Dr., Ann Arbor, MI
49109-0644; e-mail: deitzman{at}umich.edu.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction