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Transforming growth factor-beta 1 (tgf-β1) induces angiogenesis through vascular endothelial growth factor (vegf)-mediated apoptosis

Giovanni Ferrari¹, B D. Cook¹, Vitaly Terushkin¹, Giuseppe Pintucci¹, & Paolo Mignatti¹

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1. New York University School of Medicine

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Document Type:

Manuscript

Date:

Received 02 April 2008 16:49 UTC; Posted 03 April 2008

Subjects:

Cancer

Tags:

• endothelial cells
• angiogenesis
• TGF-beta1
• VEGF
• apoptosis

Abstract:

VEGF and TGF-β1 induce angiogenesis but have opposing effects on endothelial cells. VEGF protects endothelial cells from apoptosis; TGF-β1 induces apoptosis. We have previously shown that VEGF / VEGF receptor-2 (flk-1) signaling mediates TGF-β1 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-β1 induction of angiogenesis. In vitro the apoptotic effect of TGF-β1 on endothelial cells is rapid and followed by a long period in which the cells are refractory to apoptosis induction by TGF-β1. Inhibition of VEGF / flk-1 signaling abrogates formation of vessel-like structures by TGF-β1 with an effect comparable to that of z-VAD, an apoptosis inhibitor. Similarly, genetic deficiency of VEGF abolishes TGF-β1 upregulation of endothelial cell differentiation and formation of vascular structures in embryoid bodies. In vivo TGF-β1 induces endothelial cell apoptosis as rapidly as in vitro. Inhibition of VEGF blocks TGF-β1 induction of both apoptosis and angiogenesis, an effect similar to that of z-VAD. Thus, TGF-β1 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.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Ferrari, Giovanni, Cook, B, Terushkin, Vitaly, Pintucci, Giuseppe, and Mignatti, Paolo. Transforming growth factor-beta 1 (tgf-β1) induces angiogenesis through vascular endothelial growth factor (vegf)-mediated apoptosis. Available from Nature Precedings <http://dx.doi.org/10.1038/npre.2008.1758.1> (2008)

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