title: Vascular endothelial growth factor receptor-2-induced initial endothelial cell migration depends on the presence of the urokinase receptor.
abstract: The angiogenic response of endothelial cells initiated by different growth factors is accompanied by assembly of cell surface-bound proteolytic machinery as a prerequisite for focal invasion. We have shown previously how the vascular endothelial growth factor (VEGF) initiates proteolysis by activation of pro-urokinase (pro-PA) via the VEGF receptor-2 (VEGFR-2). We now show that the cell surface receptor of the uPA-system, the urokinase receptor (uPAR), is redistributed to focal adhesions at the leading edge of endothelial cells in response to VEGF. VEGF165 and VEGF-E, both interacting with VEGFR-2, but not PlGF exclusively stimulating VEGFR-1, induce within minutes internalization of uPAR via an LDL receptor-like molecule, dependent on generation of active uPA and the presence of plasminogen activator inhibitor-1 (PAI-1). uPAR seems to play a pivotal role in VEGFR-2-induced endothelial cell migration because cleavage of surface uPAR impaired the migratory response of endothelial cells toward VEGF-E, but not toward PlGF.
authors.affiliation: Department of Vascular Biology and Thrombosis Research, University of Vienna, Austria.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Prager
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Breuss
authors.forename: Stefan
authors.initials: S
authors.lastname: Steurer
authors.forename: Damla
authors.initials: D
authors.lastname: Olcaydu
authors.forename: Judit
authors.initials: J
authors.lastname: Mihaly
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Brunner
authors.forename: Hannes
authors.initials: H
authors.lastname: Stockinger
authors.forename: Bernd R
authors.initials: BR
authors.lastname: Binder
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D053504:Matrix Metalloproteinases, Membrane-Associated; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics; D011506:Proteins / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*; D014764:Viral Proteins / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D016023:Integrins; D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C524898:PLAUR protein, human; C490827:Pigf protein, mouse; D017395:Plasminogen Activator Inhibitor 1; C524899:Plaur protein, mouse; D011506:Proteins; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; C084758:VEGF-like protein, Orf virus; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014764:Viral Proteins; C467480:vascular endothelial growth factor A, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D043265:Phosphatidylinositol Diacylglycerol-Lyase