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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Movement / drug effects
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Cells, Cultured / drug effects
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Endothelial Cells / cytology*
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Endothelium, Vascular / cytology*
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Endothelium, Vascular / drug effects
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Enzyme Inhibitors / pharmacology
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Female
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Focal Adhesions / metabolism
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Humans
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Integrins / physiology
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Matrix Metalloproteinase 2 / physiology
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Matrix Metalloproteinases, Membrane-Associated
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Membrane Proteins
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Metalloendopeptidases / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Oligodeoxyribonucleotides, Antisense / pharmacology
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Phosphatidylinositol Diacylglycerol-Lyase
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Plasminogen Activator Inhibitor 1 / deficiency
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Plasminogen Activator Inhibitor 1 / genetics
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Proteins / pharmacology
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / physiology*
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Receptors, Urokinase Plasminogen Activator
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Recombinant Proteins / pharmacology
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / physiology*
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Viral Proteins / pharmacology
Substances
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Enzyme Inhibitors
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Integrins
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Membrane Proteins
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Oligodeoxyribonucleotides, Antisense
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PLAUR protein, human
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Pigf protein, mouse
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Plasminogen Activator Inhibitor 1
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Plaur protein, mouse
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Proteins
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Receptors, Cell Surface
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Receptors, Urokinase Plasminogen Activator
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Recombinant Proteins
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VEGF-like protein, Orf virus
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Viral Proteins
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vascular endothelial growth factor A, mouse
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Vascular Endothelial Growth Factor Receptor-2
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases
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Matrix Metalloproteinase 2
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Phosphatidylinositol Diacylglycerol-Lyase