title: Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin.
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 alpha(v)beta3 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 alpha(v)beta3 integrin-mediated cell adhesion to vitronectin but promotes alpha5beta1-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.
authors.affiliation: Department of Pediatrics, Childrens Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
authors.forename: C
authors.initials: C
authors.lastname: Isogai
authors.forename: W E
authors.initials: WE
authors.lastname: Laug
authors.forename: H
authors.initials: H
authors.lastname: Shimada
authors.forename: P J
authors.initials: PJ
authors.lastname: Declerck
authors.forename: M F
authors.initials: MF
authors.lastname: Stins
authors.forename: D L
authors.initials: DL
authors.lastname: Durden
authors.forename: A
authors.initials: A
authors.lastname: Erdreich-Epstein
authors.forename: Y A
authors.initials: YA
authors.lastname: DeClerck
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D005353:Fibronectins / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D019096:Vitronectin / Q000494:pharmacology
chemical_list: D005353:Fibronectins; D016023:Integrins; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D019096:Vitronectin