Vascular endothelial growth factor (VEGF) induces rapid prourokinase (pro-uPA) activation on the surface of endothelial cells.
Vascular endothelial growth factor (VEGF) is the pivotal angiogenic growth factor activating endothelial cells to migrate, proliferate, and form capillary tubes. For an ordered endothelial cell migration, tissue invasion, and degradation of the extracellular matrix, proteolytic machinery is indispensable. Such machinery, suitable for localized proteolysis, is provided by the prourokinase-urokinase-plasmin system. Prourokinase (pro-uPA), the initial component of this system, is, however, synthesized in its inactive precursor form and as such bound to its cellular receptor uPAR. Here we identify a mechanism via which VEGF(165) interacting with its receptor VEGFR-2 rapidly induces prourokinase activation that is dependent on a change in integrin affinity, activation of matrix metalloproteinase 2 (MMP-2), and pro-uPA being bound to its surface receptor uPAR. This VEGF-induced pro-uPA activation on endothelial cells is responsible for VEGF-dependent local fibrinolytic activity and might be one of the initial steps in the angiogenic process.
Prager
Gerald W
GW
Department of Vascular Biology and Thrombosis Research, Schwarzspanierstrasse 17, A-1090 Vienna, Austria.
Breuss
Johannes M
JM
Steurer
Stefan
S
Mihaly
Judit
J
Binder
Bernd R
BR
D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism* / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D016023:Integrins; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; C067551:saruplase