Plasminogen activator inhibitor 1 (PAI-1) inhibits plasminogen activators (u-PA and t-PA) by forming stable complexes endocytosed via a low-density lipoprotein receptor superfamily member-dependent mechanism. PAI-1 circulates actively in plasma and latently in platelets but is also secreted and deposited into the matrix by several cells, where it participates in tissue repair processes.

Vascular endothelial growth factor (VEGF) is the pivotal angiogenic growth factor activating endothelial cells to migrate, proliferate, and form capillary tubes. For an ordered endothelial cell migration, tissue invasion, and degradation of the extracellular matrix, proteolytic machinery is indispensable. Such machinery, suitable for localized proteolysis, is provided by the prourokinase-urokinase-plasmin system. Prourokinase (pro-uPA), the initial component of this system, is, however, synthesized in its inactive precursor form and as such bound to its cellular receptor uPAR. Here we identify a mechanism via which VEGF 165 interacting with its receptor VEGFR-2 rapidly induces prourokinase activation that is dependent on a change in integrin affinity, activation of matrix metalloproteinase 2 (MMP-2), and pro-uPA being bound to its surface receptor uPAR. This VEGF-induced pro-uPA activation on endothelial cells is responsible for VEGF-dependent local fibrinolytic activity and might be one of the initial steps in the angiogenic process. (Blood. 2004;103:955-962)

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. VEGF 165 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.

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