Published online before print May 6, 2004, doi: 10.1161/01.RES.0000131498.36194.6b
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Submitted on December 30, 2003
Revised on April 22, 2004
Accepted on April 27, 2004
Vascular Endothelial Growth Factor Receptor-2-Induced Initial Endothelial Cell Migration Depends on the Presence of the Urokinase Receptor
Gerald W. Prager ;
From the Department of Vascular Biology and Thrombosis Research (G.W.P., J.M.B., S.S., D.O., J.M., P.M.B., B.R.B.), University of Vienna, Vienna, Austria; K-plus competence centre for Bio Molecular Therapeutics (J.M.B., H.S., B.R.B.), BMT, Vienna, Austria; and the Institute of Immunology (H.S.), Vienna International Research Cooperation Center at Novartis Forschungs-Institut, University of Vienna, Vienna, Austria.
* To whom correspondence should be addressed. E-mail: bernd.binder{at}univie.ac.at.
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 or 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.
Key words: angiogenesis • VEGF • urokinase receptor
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