uPAR A modulator of VEGF-induced angiogenesis

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 alpha(5)beta(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 alpha(5)beta(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 alpha(5)beta(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.