Angiogenesis, Metastasis, and the Cellular Microenvironment TGF-b1 Induces Endothelial Cell Apoptosis by Shifting VEGF Activation of p38 from the Prosurvival p38b to Proapoptotic p38a

TGF-b1 and VEGF, both angiogenesis inducers, have opposing effects on vascular endothelial cells. TGF-b1 induces apoptosis; VEGF induces survival. We have previously shown that TGF-b1 induces endothelial cell expression of VEGF, which mediates TGF-b1 induction of apoptosis through activation of p38mitogen-activated protein kinase (MAPK). Because VEGF activates p38 but protects the cells from apoptosis, this finding suggested that TGF-b1 converts p38 signaling from prosurvival to proapoptotic. Four isoforms of p38 —a, b, g , and d—have been identified. Therefore, we hypothesized that different p38 isoforms control endothelial cell apoptosis or survival, and that TGF-b1 directs VEGF activation of p38 from a prosurvival to a proapoptotic isoform.Here, we report that cultured endothelial cells express p38a, b, and g . VEGF activates p38b, whereas TGF-b1 activates p38a. TGF-b1 treatment rapidly induces p38a activation and apoptosis. Subsequently, p38a activation is downregulated, p38b is activated, and the surviving cells become refractory to TGF-b1 induction of apoptosis and proliferate. Gene silencing of p38a blocks TGF-b1 induction of apoptosis, whereas downregulation of p38b or p38g expression results in massive apoptosis. Thus, in endothelial cells p38amediates apoptotic signaling, whereas p38b and p38g transduce survival signaling. TGF-b1 activation of p38a is mediated by VEGF, which in the absence of TGF-b1 activates p38b. Therefore, these results show that TGF-b1 induces endothelial cell apoptosis by shifting VEGF signaling from the prosurvival p38b to the proapoptotic p38a. Mol Cancer Res; 1–10. 2012 AACR.