Abstract
AbstractVEGF and TGF-[beta]1 induce angiogenesis but have opposing effects on endothelial cells. VEGF protects endothelial cells from apoptosis; TGF-[beta]1 induces apoptosis. We have previously shown that VEGF / VEGF receptor-2 (flk-1) signaling mediates TGF-[beta]1 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-[beta]1 induction of angiogenesis. In vitro the apoptotic effect of TGF-[beta]1 on endothelial cells is rapid and followed by a long period in which the cells are refractory to apoptosis induction by TGF-[beta]1. Inhibition of VEGF / flk-1 signaling abrogates formation of vessel-like structures by TGF-[beta]1 with an effect comparable to that of z-VAD, an apoptosis inhibitor. Similarly, genetic deficiency of VEGF abolishes TGF-[beta]1 upregulation of endothelial cell differentiation and formation of vascular structures in embryoid bodies. In vivo TGF-[beta]1 induces endothelial cell apoptosis as rapidly as in vitro. Inhibition of VEGF blocks TGF-[beta]1 induction of both apoptosis and angiogenesis, an effect similar to that of z-VAD. Thus, TGF-[beta]1 induction of angiogenesis requires rapid and transient endothelial cell apoptosis mediated by VEGF/flk-1. This novel, unexpected role of VEGF and flk-1 indicates VEGF-mediated apoptosis as a potential target to control angiogenesis.
Highlights
Angiogenesis, the formation of capillaries from preexisting blood vessels, occurs in a variety of physiological and pathological settings, including embryonic development, wound healing and tumor growth
Because vascular endothelial growth factor (VEGF) mediates the apoptotic activity of TGF-β1 on the choriollantoic membrane (CAM) endothelial cells, these results indicated that the rapid apoptotic effect mediated by VEGF is required for TGF-β1 induction of angiogenesis in vivo
We have previously shown that the rapid induction of endothelial cell apoptosis by TGF-β1 is mediated by the autocrine or paracrine activation of VEGF receptor 2 by endothelial cell VEGF (Ferrari et al, 2006)
Summary
Angiogenesis, the formation of capillaries from preexisting blood vessels, occurs in a variety of physiological and pathological settings, including embryonic development, wound healing and tumor growth. Cytokines and growth factors upregulate VEGF expression in a variety of cell types (Goldman et al, 1993; Li et al, 1995; Pertovaara et al, 1994). Fibroblast growth factor-2 (FGF-2) and TGF-β1 induce VEGF expression in vascular endothelial cells (Ferrari et al, 2006; Seghezzi et al, 1998). VEGF, flk-1, and flt-1 are indispensable for angiogenesis and their genetic deficiency causes embryonic lethality as a result of blood vessels disorganization, endothelial cell overgrowth or impaired endothelial cell development (Carmeliet et al, 1996; Ferrara et al, 1996). Inhibition of VEGF results in decreased tumor vascularity and growth, implicating VEGF as the major tumor angiogenesis factor (Ferrara, 2004). Pharmacological treatments targeting VEGF or VEGFR-2 are currently used or in advanced clinical trials for the therapy of several malignancies (Ferrara, 2004; Ferrara and Kerbel, 2005)
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