Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis.
VEGF and TGF-beta1 induce angiogenesis but have opposing effects on endothelial cells. VEGF protects endothelial cells from apoptosis; TGF-beta1 induces apoptosis. We have previously shown that VEGF/VEGF receptor-2 (VEGFR2) signaling mediates TGF-beta1 induction of apoptosis. This finding raised an important question: Does this mechanism stimulate or inhibit angiogenesis? Here we report that VEGF-mediated apoptosis is required for TGF-beta1 induction of angiogenesis. In vitro the apoptotic effect of TGF-beta1 on endothelial cells is rapid and followed by a long period in which the cells are refractory to apoptosis induction by TGF-beta1. Inhibition of VEGF/VEGFR2 signaling abrogates formation of cord-like structures by TGF-beta1 with an effect comparable to that of z-VAD, an apoptosis inhibitor. Similarly, genetic deficiency of VEGF abolishes TGF-beta1 upregulation of endothelial cell differentiation and formation of vascular structures in embryoid bodies. In vivo TGF-beta1 induces endothelial cell apoptosis as rapidly as in vitro. Inhibition of VEGF blocks TGF-beta1 induction of both apoptosis and angiogenesis, an effect similar to that of z-VAD. Thus, TGF-beta1 induction of angiogenesis requires a rapid and transient apoptotic effect mediated by VEGF/VEGFR2. This novel, unexpected role of VEGF and VEGFR2 indicates VEGF-mediated apoptosis as a potential target to control angiogenesis.
Ferrari
Giovanni
G
The Seymour Cohn Cardiovascular Research Laboratory, Department of Cardiothoracic Surgery, New York, New York 10016, USA.
Cook
Brandoch D
BD
Terushkin
Vitaly
V
Pintucci
Giuseppe
G
Mignatti
Paolo
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002196:Capillaries / Q000033:anatomy & histology / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2