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Plasminogen Activator Inhibitor-1 Promotes Angiogenesis by Stimulating Endothelial Cell Migration toward Fibronectin¹

Departments of Pediatrics [C. I., W. E. L., M. F. S., D. L. D., A. E-E., Y. A. D.], Pathology [H. S.], and Biochemistry and Molecular Biology [Y. A. D.], Childrens Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California 90027, and Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium [P. J. D.]

Increased expression of plasminogen activator inhibitor-1 (PAI-1) in cancer patients is associated with unfavorable outcome, and the reason for this paradox has been poorly understood. We have previously reported elevated levels of PAI-1 in primary tumors of advanced neuroblastomas (Y. Sugiura et al., Cancer Res., 59: 1327–1336, 1999). Here we demonstrate that PAI-1 is coexpressed with the angiogenesis marker _vß₃ integrin in blood vessels of primary neuroblastoma tumors, suggesting that PAI-1 plays a role in angiogenesis. Using human brain microvascular endothelial cells (HBMECs), we found that PAI-1 inhibits _vß₃ integrin-mediated cell adhesion to vitronectin but promotes ₅ß₁-mediated migration from vitronectin toward fibronectin. Inhibition of vitronectin adhesion by PAI-1 did not induce HBMEC apoptosis. PAI-1 also inhibited endothelial tube formation on Matrigel in the presence of vitronectin but had a stimulatory effect in the presence of fibronectin. This effect of PAI-1 on microvascular endothelial cells is primarily related to the ability of PAI-1 to bind to vitronectin via its NH₂-terminal domain and to interfere with cell adhesion to vitronectin. We propose that PAI-1 acts as a positive switch for angiogenesis by promoting endothelial cell migration away from their vitronectin-containing perivascular space toward fibronectin-rich tumor tissue. These observations provide a novel explanation for the enhancing effect of PAI-1 in cancer progression.

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