VEGF, a prosurvival factor, acts in concert with TGF-beta1 to induce endothelial cell apoptosis.
VEGF and TGF-beta1 are potent angiogenesis inducers with opposing effects on endothelial cells. TGF-beta1 induces apoptosis; VEGF protects endothelial cells from apoptosis. We found that TGF-beta1 promotes endothelial cell expression of FGF-2, which up-regulates VEGF synthesis. Inhibition of VEGF signaling through VEGF receptor 2 (flk-1) abrogates TGF-beta1-induced apoptosis and p38(MAPK) activation. Inhibition of p38(MAPK) blocks TGF-beta1-induced apoptosis, showing that VEGF/flk-1-mediated activation of p38(MAPK) is required for TGF-beta1 induction of apoptosis. In the absence of TGF-beta1, VEGF activates p38(MAPK) and promotes endothelial cell survival. However, in context with TGF-beta1, VEGF/flk-1-mediated activation of p38(MAPK) results in apoptosis. Thus, cross-talk between TGF-beta1 and VEGF signaling converts VEGF/flk-1-activated p38(MAPK) into a proapoptotic signal. This finding illustrates an unexpected role of VEGF and indicates that VEGF can be pharmacologically converted into an apoptotic factor, a novel approach to antiangiogenesis therapy.
Ferrari
Giovanni
G
The Seymour Cohn Cardiovascular Research Laboratory, Department of Cardiothoracic Surgery, New York University School of Medicine, New York, NY 10016, USA.
Pintucci
Giuseppe
G
Seghezzi
Graziano
G
Hyman
Kevin
K
Galloway
Aubrey C
AC
Mignatti
Paolo
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D040301:Vascular Endothelial Growth Factor Receptor-2; D048051:p38 Mitogen-Activated Protein Kinases