Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin

Chiho Isogai, Walter E. Laug, Hiroyuki Shimada, Paul J. Declerck, Monique F. Stins, Donald L. Durden, Anat Erdreich-Epstein, Yves A. DeClerck

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

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 αvβ3 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 αvβ3 integrin-mediated cell adhesion to vitronectin but promotes α5β1-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.

Original languageEnglish (US)
Pages (from-to)5587-5594
Number of pages8
JournalCancer Research
Volume61
Issue number14
StatePublished - Jul 15 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Isogai, C., Laug, W. E., Shimada, H., Declerck, P. J., Stins, M. F., Durden, D. L., Erdreich-Epstein, A., & DeClerck, Y. A. (2001). Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Research, 61(14), 5587-5594.