Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor tha t has been shown to act as an endothelial cell mitogen as well as a vascula r permeability factor. Several recent reports have also implicated VEGF as a major survival factor for endothelial cells during angiogenesis and vascu logenesis along with other growth factors such as bFGF and angiopoietin-1. VEGF has been shown to mediate this additional function, at least in part t hrough the induction of bcl-2 and the activation of the PI3 kinase-Akt/PKB signaling pathway. We report here that VEGF can also mediate the induction/ upregulation of members of a newly discovered family of antiapoptotic prote ins, namely the (I) under bar nhibitors of <(Ap)under bar>optosis (IAP), in vascular endothelial cells. We show that VEGF(165) leads to the induction of XIAP (2.9-fold) and survivin (19.1-fold) protein in human umbilical vein endothelial cells (HUVECs), In contrast, bFGF had little effect on XIAP ex pression, but produced approximately a 10-fold induction on survivin. VEGF- dependent upregulation of survivin could be prevented by cell cycle arrest in the G1 and S phases. These findings implicate that the survival and mito tic functions of VEGF in an angiogenic context may be more intrinsically re lated than previously anticipated. Moreover, they also raise the possibilit y of therapeutically targeting XIAP or survivin in antiangiogenic therapy a s a means of suppressing tumor growth, in addition to directly targeting tu mor cells which express these survival proteins. (C) 1999 Academic Press.