Title: The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent
Authors: Devy, Laetitia ×
Blacher, Silvia
Grignet-Debrus, Christine
Bajou, Khalid
Masson, Veronique
Gerard, Robert D
Gils, Ann
Carmeliet, Geert
Carmeliet, Peter
Declerck, Paul
Nöel, Agnès
Foidart, Jean-Michel #
Issue Date: Jan-2002
Publisher: The Federation of American Societies for Experimental Biology
Series Title: FASEB Journal vol:16 issue:2 pages:147-54
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.
ISSN: 0892-6638
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
Molecular and Vascular Biology
Laboratory for Pharmaceutical Biology (-)
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)
× corresponding author
# (joint) last author

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