Abstract
Vascular endothelial growth factor (VEGF)-initiated angiogenesis requires both coordinated proteolytic degradation of extracellular matrix provided by the urokinase plasminogen activator/urokinase receptor (uPA/uPAR) system and regulation of cell-migration provided by integrin-matrix interaction. Previously we have shown that stimulation of pericellular proteolysis induced by VEGF occurs via the VEGF receptor-2 leading to redistribution of uPAR to focal adhesions at the leading edge of endothelial cells. In our recent work published in Cardiovascular Research, we investigated the mechanisms underlying the uPAR-dependent modulation of VEGF-induced endothelial migration. By applying a micropatterning technique we described that VEGF stimulation results in complex formation between uPAR and α 5β 1-integrin on the cell surface. The subsequent internalization of this complex, important for receptor redistribution, was demonstrated by flow-cytometry and immunohistochemistry. Targeting of the interaction site between uPAR and α 5β 1 impairs receptor internalization and leads to the inhibition of endothelial cell migration in vitro and in an angiogenesis model in vivo. This proof-of-principle that the interface of uPAR and α 5β 1-integrin may represent a promising site to therapeutically target tumor angiogenesis raises hope for the development of an anti-angiogenic approach that is limited to only the mobilizing effect of VEGF to endothelial cells, and does not interfere with the inarguably positive effect of VEGF as survival factor.