Urokinase mediates endothelial cell survival via induction of the X-linked inhibitor of apoptosis protein

Urokinase-type plasminogen activator (uPA) additionally elicits a whole array of pro-angiogenic responses, such as differentiation, proliferation, and migration. In this study, we demonstrate that in endothelial cells uPA also protects against apoptosis by transcriptional upregulation and partially by mRNA stabilization of inhibitor of apoptosis proteins, most prominently the X-linked inhibitor of apoptosis protein (XIAP). The antiapoptotic activity of uPA was dependent on its protease activity, the presence of uPA receptor (uPAR) and low-density lipoprotein receptor-related protein (LRP), but independent of the phosphatidylinositol 3 (PI3) kinase pathway, whereas vascular endothelial growth factor (VEGF) induced antiapoptosis was PI3 kinase dependent. uPA-induced cell survival involved phosphorylation of p21-activated kinase 1 (Pak1) and the I kappa B kinase alpha that leads to nuclear factor kappa B (NF-kappa B) p52 activation. Indeed, blocking NF-kappa B activation by using specific NF-kappa B inhibitors abolished uPA-induced cell survival as it blocked uPA-induced XIAP up-regulation. Furthermore, down-regulating XIAP expression by small interfering RNA(siRNA) significantly reduced uPA-dependent endothelial cell survival. This mechanism is also important for VEGF-induced antiapoptosis because VEGF-dependent upregulation of XIAP was found defective in uPA(-/-) endothelial cells. This led us to conclude that uPA is part of a novel NF-kappa B-dependent cell survival pathway. (Blood. 2009; 113: 1383-1390)