TGF-β1 Induces Endothelial Cell Apoptosis by Shifting VEGF Activation of p38MAPK from the Prosurvival p38β to Proapoptotic p38α

TGF-beta 1 and VEGF, both angiogenesis inducers, have opposing effects on vascular endothelial cells. TGF-beta 1 induces apoptosis; VEGF induces survival. We have previously shown that TGF-beta 1 induces endothelial cell expression of VEGF, which mediates TGF-beta 1 induction of apoptosis through activation of p38 mitogen-activated protein kinase (MAPK). Because VEGF activates p38(MAPK) but protects the cells from apoptosis, this finding suggested that TGF-beta 1 converts p38(MAPK) signaling from prosurvival to proapoptotic. Four isoforms of p38(MAPK)-alpha, beta, gamma, and delta-have been identified. Therefore, we hypothesized that different p38(MAPK) isoforms control endothelial cell apoptosis or survival, and that TGF-beta 1 directs VEGF activation of p38(MAPK) from a prosurvival to a proapoptotic isoform. Here, we report that cultured endothelial cells express p38 alpha, beta, and gamma. VEGF activates p38 beta, whereas TGF-beta 1 activates p38 alpha. TGF-beta 1 treatment rapidly induces p38 alpha activation and apoptosis. Subsequently, p38 beta activation is downregulated, p38 beta is activated, and the surviving cells become refractory to TGF-beta 1 induction of apoptosis and proliferate. Gene silencing of p38 alpha blocks TGF-beta 1 induction of apoptosis, whereas downregulation of p38 beta or p38 gamma expression results in massive apoptosis. Thus, in endothelial cells p38 alpha mediates apoptotic signaling, whereas p38 beta and p38 gamma transduce survival signaling. TGF-beta 1 activation of p38 alpha is mediated by VEGF, which in the absence of TGF-beta 1 activates p38 beta. Therefore, these results show that TGF-beta 1 induces endothelial cell apoptosis by shifting VEGF signaling from the prosurvival p38 beta to the proapoptotic p38 alpha. Mol Cancer Res; 10(5); 605-14. (C) 2012 AACR.