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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-04-1237.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 3960-3968
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Src and phosphatidylinositol 3-kinase mediate
soluble E-selectin-induced angiogenesis
Pawan Kumar,
Mohammad A. Amin,
Lisa A. Harlow,
Peter J. Polverini, and
Alisa E. Koch
From the Veterans Administration, Lakeside
Division, Chicago Health Care System, Chicago, IL; the Department of
Medicine, Northwestern University Medical School, Chicago, IL; and the
Department of Oral Sciences, University of Minnesota School of
Dentistry, Minneapolis, MN.
Angiogenesis plays an important role in a variety of
pathophysiologic processes, including tumor growth and rheumatoid
arthritis. We have previously shown that soluble E-selectin
(sE-selectin) is an important angiogenic mediator. However, the
mechanism by which sE-selectin mediates angiogenesis is still unknown.
In this study, we show that sE-selectin is a potent mediator of human dermal microvascular endothelial cell (HMVEC) chemotaxis, which is
predominantly mediated through the Src and the phosphatidylinositiol 3-kinase (PI3K) pathways. Further, sE-selectin induced a 2.2-fold increase in HMVEC tube formation in the Matrigel in vitro assay. HMVECs pretreated with the Src inhibitor (PP2) and the PI3K
inhibitor (LY294002) or transfected with Src antisense oligonucleotides or Akt dominant-negative mutants significantly inhibited
sE-selectin-mediated HMVEC tube formation. In contrast, HMVECs
transfected with an extracellular signal-related kinase 1/2
(ERK1/2) mutant or pretreated with the mitogen-activated
protein kinase (MAPK) inhibitor PD98059 failed to show
sE-selectin-mediated HMVEC tube formation. Similarly, in the
Matrigel-plug in vivo assay, sE-selectin induced a 2.2-fold increase in
blood vessel formation, which was significantly inhibited by PP2 and
LY294002 but not by PD98059. sE-selectin induced a marked
increase in Src, ERK1/2, and PI3K phosphorylation. PI3K and ERK1/2
phosphorylation was significantly inhibited by PP2, thereby suggesting
that both of these pathways may be activated via Src kinase. Even
though the ERK1/2 pathway was activated by sE-selectin in HMVECs, it
seems not to be essential for sE-selectin-mediated angiogenesis. Taken
together, our data clearly show that sE-selectin-induced angiogenesis
is predominantly mediated through the Src-PI3K pathway.
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