Vascular endothelial growth factor enhances the expression of urokinase receptor in human endothelial cells via protein kinase C activation.
Among other proteolytic enzymes, the urokinase-type plasminogen activator (u-PA)/plasmin cascade contributes to cell migration and the formation of capillary-like structures in a fibrinous exudate. The u-PA receptor (u-PAR) focuses proteolytical activity on the cell surface of the endothelial cell and hereby accelerates the pericellular matrix degradation. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2 enhance u-PA receptor expression in human endothelial cells. In this paper we show that the protein kinase C (PKC) inhibitors Ro31-8220 and GF109203X inhibit VEGF165-induced u-PAR antigen expression in human endothelial cells, whereas PKC inhibition had no effect on FGF-2-induced u-PAR antigen enhancement. In addition, inhibition of PKC activity had no effect on VEGF165- or FGF-2-induced proliferation in human endothelial cells. We conclude that VEGF165 induces u-PAR via a PKC-dependent pathway, whereas proliferation is induced via a different pathway probably involving tyrosine phosphorylation of proteins downstream of the VEGF receptors.
Gaubius Laboratory TNO-PG, Leiden, The Netherlands.
M E
ME
Kroon
P
P
Koolwijk
M A
MA
Vermeer
B
B
van der Vecht
V W
VW
van Hinsbergh
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000494:pharmacology* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology* / Q000502:physiology; D008301:Maleimides / Q000494:pharmacology; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000187:drug effects*; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007211:Indoles; D008222:Lymphokines; D008301:Maleimides; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005346:Fibroblast Growth Factors; D011493:Protein Kinase C; D010960:Plasminogen Activators; C070515:bisindolylmaleimide I; C064758:Ro 31-8220