VEGF 165 , the major angiogenic growth factor, is known to activate various steps in proangiogenic endothelial cell behavior, such as endothelial cell migration and invasion, or endothelial cell survival. Thereby, the urokinase-type plasminogen activator (uPA) system has been shown to play an essential role not only by its proteolytic capacities, but also by induction of intracellular signal transduction. Therefore, expression of its cell surface receptor uPAR is thought to be an essential regulatory mechanism in angiogenesis. We found that uPAR expression on the surface of confluent endothelial cells was down-regulated compared with subconfluent proliferating endothelial cells. Regulation of uPAR expression was most probably affected by extracellular signalregulated kinase 1/2 (ERK1/2) activation, a downstream signaling event of the VEGF/VEGF-receptor system. Consistently, the receptor-like protein tyrosine phosphatase DEP-1 (density enhanced phosphatase IntroductionAngiogenesis is currently in the focus of basic and translational research: a detailed analysis of the complex mechanisms involved in its regulation led to various therapeutic concepts 1 in oncology for tumor angiogenesis, ophthalmology as in macular degeneration or choroidal neovascular disease, rheumatology in pannus formation, or dermatology for psoriasis.We have demonstrated previously that initial steps of angiogenesis are dependent on vascular endothelial growth factor receptor-2 (VEGFR-2) induced pro-urokinase (pro-uPA) activation. 2 Thereby, pro-uPA bound to its glycosylphosphatidylinositol-anchored cell surface receptor uPAR becomes activated, a process that involves integrin-dependent membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 activation in a phosphatidylinositol-3 kinase-dependent manner. 2,3 Active uPA in turn is blocked by its specific inhibitor plasminogen activator inhibitor-1 (PAI-1). The so-formed ternary complex uPAR-uPA-PAI-1 becomes internalized via a low-density lipoprotein-receptor like molecule. 4,5 Apart from an eminent role of uPAR in cancer cell biology, 6-9 this aforementioned process seems to mediate VEGF-induced endothelial cell (EC) migration in vitro as well as angiogenesis in vivo as shown by a Matrigel plaque angiogenesis assay. 2 Furthermore, uPA was shown to mediate EC survival via induction of the X-linked inhibitor of apoptosis protein, a process that is also dependent on uPAR. 10 These data suggest that the amount of cell surface uPAR is affecting (1) the initial migratory response of ECs toward angiogenic stimulation 11 and (2) EC survival during angiogenesis. Thereby, it is known that activation of somatic cells, 12 and specifically of ECs 13,14 by growth factors, is greatly limited when cells are grown to confluence.In this study, we show that uPAR surface expression is dependent on EC density. Thereby, density enhanced phosphatase-1 (DEP-1) negatively regulates extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, which is involved in uPAR protein expression. These ...
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