Transforming growth factor-beta 1 (tgf-β1) induces angiogenesis through vascular endothelial growth factor (vegf)-mediated apoptosis

VEGF and TGF-[beta]1 induce angiogenesis but have opposing effects on endothelial cells. VEGF protects endothelial cells from apoptosis; TGF-[beta]1 induces apoptosis. We have previously shown that VEGF / VEGF receptor-2 (flk-1) signaling mediates TGF-[beta]1 induction of apoptosis. This finding raised an important question: Does this mechanism stimulate or inhibit angiogenesis? Here we report that VEGF-mediated apoptosis is required for TGF-[beta]1 induction of angiogenesis. In vitro the apoptotic effect of TGF-[beta]1 on endothelial cells is rapid and followed by a long period in which the cells are refractory to apoptosis induction by TGF-[beta]1. Inhibition of VEGF / flk-1 signaling abrogates formation of vessel-like structures by TGF-[beta]1 with an effect comparable to that of z-VAD, an apoptosis inhibitor. Similarly, genetic deficiency of VEGF abolishes TGF-[beta]1 upregulation of endothelial cell differentiation and formation of vascular structures in embryoid bodies. In vivo TGF-[beta]1 induces endothelial cell apoptosis as rapidly as in vitro. Inhibition of VEGF blocks TGF-[beta]1 induction of both apoptosis and angiogenesis, an effect similar to that of z-VAD. Thus, TGF-[beta]1 induction of angiogenesis requires rapid and transient endothelial cell apoptosis mediated by VEGF/flk-1. This novel, unexpected role of VEGF and flk-1 indicates VEGF-mediated apoptosis as a potential target to control angiogenesis.