title: TGF-β1 induces endothelial cell apoptosis by shifting VEGF activation of p38(MAPK) from the prosurvival p38β to proapoptotic p38α.
abstract: TGF-β1 and 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 prosurvival to a proapoptotic isoform. Here, we report that cultured endothelial cells express p38α, β, and γ. VEGF activates p38β, whereas TGF-β1 activates p38α. TGF-β1 treatment rapidly induces p38α activation and apoptosis. Subsequently, p38α activation is downregulated, p38β is activated, and the surviving cells become refractory to TGF-β1 induction of apoptosis and proliferate. Gene silencing of p38α blocks TGF-β1 induction of apoptosis, whereas downregulation of p38β or p38γ expression results in massive apoptosis. Thus, in endothelial cells p38α mediates apoptotic signaling, whereas p38β and p38γ transduce survival signaling. TGF-β1 activation of p38α is mediated by VEGF, which in the absence of TGF-β1 activates p38β. Therefore, these results show that TGF-β1 induces endothelial cell apoptosis by shifting VEGF signaling from the prosurvival p38β to the proapoptotic p38α.
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferrari
authors.forename: Vitaly
authors.initials: V
authors.lastname: Terushkin
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wolff
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Cristina
authors.initials: C
authors.lastname: Valacca
authors.forename: Paolo
authors.initials: P
authors.lastname: Poggio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pintucci
authors.forename: Paolo
authors.initials: P
authors.lastname: Mignatti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002417:Cattle; D002470:Cell Survival / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D048290:Mitogen-Activated Protein Kinase 11 / Q000235:genetics / Q000378:metabolism*; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D048291:Mitogen-Activated Protein Kinase 12; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14