TGF-β1 INDUCES ENDOTHELIAL CELL APOPTOSIS BY SHIFTING VEGF ACTIVATION OF p38MAPK FROM THE PRO-SURVIVAL p38β TO PRO-APOPTOTIC p38α

摘要

Transforming growth factor-beta1 (TGF-β1) and vascular endothelial growth factor (VEGF), both angiogenesis inducers, have opposing effects on vascular endothelial cells. TGF-β1 induces apoptosis; VEGF induces survival. We have previously shown that TGF-β1 induces endothelial cell expression of VEGF, which mediates TGF-β1 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-β1 converts p38^MAPK signaling from prosurvival to proapoptotic. Four isoforms of p38^MAPK - α, β, γ and δ – have been identified. Therefore, we hypothesized that different p38^MAPK isoforms control endothelial cell apoptosis or survival, and that TGF-β1 directs VEGF activation of p38^MAPK from a pro-survival to a proapoptotic isoform. Here we report that cultured endothelial cells express p38 α, β and γ. VEGF activates p38 β, whereas TGF-β1 activates p38 α. TGF-β1 treatment rapidly induces p38 α activation and apoptosis. Subsequently, p38 α activation is downregulated, p38 β is activated, and the surviving cells become refractory to TGF-β1 induction of apoptosis and proliferate. Gene silencing of p38 α blocks TGF-β1 induction of apoptosis, whereas downregulation of p38 β or p38 γ expression results in massive apoptosis. Thus, in endothelial cells p38 α mediates apoptotic signaling, whereas p38 β and p38 γ transduce survival signaling. TGF-β1 activation of p38 α is mediated by VEGF, which in the absence of TGF-β1 activates p38 β. Therefore, these results show that TGF-β1 induces endothelial cell apoptosis by shifting VEGF signaling from the prosurvival p38 β to the proapoptotic p38 α.