Vascular endothelial growth factor receptor-2-induced initial endothelial cell migration depends on the presence of the urokinase receptor.
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.
Prager
Gerald W
GW
Department of Vascular Biology and Thrombosis Research, University of Vienna, Austria.
Breuss
Johannes M
JM
Steurer
Stefan
S
Olcaydu
Damla
D
Mihaly
Judit
J
Brunner
Patrick M
PM
Stockinger
Hannes
H
Binder
Bernd R
BR
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
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