Antiapoptotic Activity of Vascular Endothelial Growth Factor (VEGF) Is also Mediated by VEGF Induced Pro-urokinase (Pro-uPA) Activation

Abstract number: P1157

Prager GW, Koschelnick Y, Leitner K, Brunner P, Binder BR

We could show previously (Prager et al Blood 2004) that VEGF induces not only transcriptional upregulation of pro-uPA, but also its activation to the active serine protease uPA. That activation is mediated by VEGFR2 and downstream PI3-kinase and involves integrin deactivation and MT-1MMP and MMP2. Active uPA in turn does not only provide the necessary proteolytic machinery for invasion of the extracellular matrix by angiogenic stimulated endothelial cells but is also a prerequisite for redistribution of the uPA receptor (uPAR) together with integrins and endothelial cell migration (Prager et al., Circ. Res. 2004). During migration endothelial cells are apoptosis prone and VEGF is known to induce cell-survival via PI3-kinase/Akt dependent phosphorylation of the pro-apoptotic proteins BAD, PED/PEA-2 or pro-caspase-9 or via inhibition of SAPKs (stress activated kinases). Here we show that active uPA also induces cell survival. uPA is capable to activate NFkB via Cdc42, its downstream effectors PAK and TAK leading to IKK-1 phosphorylation. Contrary to VEGF the uPA induced survival pathway is PI3k/Akt independent. In response to uPA-induced NFkB activation, inhibitor of apoptosis proteins (IAPs) are transciptionally upregulated most significantly the X-linked inhibitor of apoptosis protein (XIAP). Using an adenovirus overexpressing IkB to block NFkB, uPA was ineffective to induce endothelial cell survival and capillary-like tube formation on Matrigel^® was inhibited even upon stimulation by VEGF. Furthermore, both VEGF and uPA were ineffective to upregulate XIAP when uPAR/uPA/PAI-1 internalization and in turn uPA signaling was inhibited by addition of the Receptor Associate Protein (RAP). From these data we conclude that the PI3-k independent uPA-Cdc42-NFkB-XIAP survival pathway is an additional important antiapoptotic pathway induced in endothelial cells by VEGF.