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(Circulation Research. 2004;94:1562.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Vascular Endothelial Growth Factor Receptor-2–Induced Initial Endothelial Cell Migration Depends on the Presence of the Urokinase Receptor

Gerald W. Prager^*, Johannes M. Breuss^*, Stefan Steurer, Damla Olcaydu, Judit Mihaly, Patrick M. Brunner, Hannes Stockinger, Bernd R. Binder

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; K-plus competence centre for Bio Molecular Therapeutics, BMT (J.M.B., H.S., B.R.B.); and the Institute of Immunology (H.S.), Vienna International Research Cooperation Center at Novartis Forschungs-Institut, University of Vienna, Vienna, Austria.

Correspondence to Bernd R. Binder, Department of Vascular Biology and Thrombosis Research University of Vienna, Schwarzspanierstr. 17, Vienna A-1090, Austria. 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 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.

Key Words: angiogenesis • VEGF • urokinase receptor

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