The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent

Laetitia Devy, Silvia Blacher, Christine Grignet-Debrus, Khalid Bajou, Véronique Masson, Robert D. Gerard, A. N N Gils, Geert Carmeliet, Peter Carmeliet, Paul J. Declerck, Agnès Noël, Jean Michel Foidart

Research output: Contribution to journalArticle

231 Scopus citations

Abstract

Plasminogen activator inhibitor 1 (PAI-1) is believed to control proteolytic activity and cell migration during angiogenesis. We previously demonstrated in vivo that this inhibitor is necessary for optimal tumor invasion and vascularization. We also showed that PAI-1 angiogenic activity is associated with its control of plasminogen activation but not with the regulation of cell-matrix interaction. To dissect the role of the various components of the plasminogen activation system during angiogenesis, we have adapted the aortic ring assay to use vessels from gene-inactivated mice. The single deficiency of tPA", uPA, or uPAR, as well as combined deficiencies of uPA and tPA, did not dramatically affect microvessel formation. Deficiency of plasminogen delayed microvessel outgrowth. Lack of PAI-1 completely abolished angiogenesis, demonstrating its importance in the control of plasmin-mediated proteolysis. Microvessel outgrowth from PAI-1 -/- aortic rings could be restored by adding exogenous PAI-1 (wild-type serum or purified recombinant PAI-1). Addition of recombinant PAI-1 led to a bell-shaped angiogenic response clearly showing that PAI-1 is proangiogenic at physiological concentrations and antiangiogenic at higher levels. Using specific PAI-1 mutants, we could demonstrate that PAI-1 promotes angiogenesis at physiological (nanomolar) concentrations through its antiproteolytic activity rather than by interacting with vitronectin.

Original languageEnglish (US)
Pages (from-to)147-154
Number of pages8
JournalFASEB Journal
Volume16
Issue number2
DOIs
StatePublished - Feb 11 2002

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Keywords

  • Angiogenesis
  • Cell migration
  • PAI-1
  • Proteolysis
  • Serine protease

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Devy, L., Blacher, S., Grignet-Debrus, C., Bajou, K., Masson, V., Gerard, R. D., Gils, A. N. N., Carmeliet, G., Carmeliet, P., Declerck, P. J., Noël, A., & Foidart, J. M. (2002). The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB Journal, 16(2), 147-154. https://doi.org/10.1096/fj.01-0552com