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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-04-1237.
Submitted April 29, 2002
Accepted January 3, 2003
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*
Department of Medicine, Northwestern University, Chicago, IL, USA
Lakeside Division, Veterans Administration, Chicago, IL, USA
Department of Oral Sciences, University of Minnesota School of Dentistry, Minneapolis, MN, USA
* Corresponding author; email: ae-koch{at}northwestern.edu.
Angiogenesis plays an important role in a variety of pathophysiological processes, including tumor growth and rheumatoid arthritis. We have previously shown that soluble E-selectin (sE-selectin) is an important angiogenic mediator (Koch AE et al, (1995) Nature 376, 517-519). 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, 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 ERK1/2 mutant or pretreated with the 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 with 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 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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