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J. Biol. Chem., Vol. 279, Issue 41, 43352-43360, October 8, 2004

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p38 MAPK Mediates -Irradiation-induced Endothelial Cell Apoptosis, and Vascular Endothelial Growth Factor Protects Endothelial Cells through the Phosphoinositide 3-Kinase-Akt-Bcl-2 Pathway^*

Pawan Kumar, April I. Miller, and Peter J. Polverini¶

From the Department of Oral Medicine, Pathology, and Oncology, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109 and the Department of Oral Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota 55455

Therapeutic radiation is widely used in cancer treatments. The success of radiation therapy depends not only on the radiosensitivity of tumor cells but also on the radiosensitivity of endothelial cells lining the tumor vasculature. Vascular endothelial growth factor (VEGF) plays a critical role in protecting endothelial cells against a number of antitumor agents including ionizing radiation. Strategies designed to overcome the survival advantage afforded to endothelial cells by VEGF might aid in enhancing the efficacy of radiation therapy. In this report we examined the signaling cascade(s) involved in VEGF-mediated protection of endothelial cells against -irradiation. -Irradiation-induced apoptosis of human dermal microvascular endothelial cells (HDMECs) was predominantly mediated through the p38 MAPK pathway as an inhibitor of p38 MAPK (PD169316), and dominant negative mutants of p38 MAPK could significantly enhance HDMEC survival against -irradiation. Inhibition of the PI3K and MAPK pathways markedly up-regulated -irradiation-mediated p38 MAPK activation resulting in enhanced HDMEC apoptosis. In contrast, VEGF-treated HDMECs were protected from -irradiation-induced apoptosis predominantly through the PI3K/Akt pathway. Bcl-2 expression was markedly elevated in VEGF-treated HDMECs, and it was significantly inhibited by the PI3K inhibitor LY294002. HDMECs exposed to irradiation showed a significant decrease in Bcl-2 expression. In contrast, VEGF-stimulated HDMECs, when irradiated, maintained higher levels of Bcl-2 expression. Taken together our results suggest that -irradiation induces endothelial cell apoptosis predominantly via the activation of p38 MAPK, and VEGF protects endothelial cells against -irradiation predominantly via the PI3K-Akt-Bcl-2 signaling pathway.

Received for publication, May 24, 2004 , and in revised form, July 29, 2004.

^* This work was supported by National Institutes of Health Grant DE 13161 (to P. J. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: The University of Michigan School of Dentistry, 1011 N. University Ave., Rm. 1234, Ann Arbor, MI 48109. Tel.: 734-763-3311; Fax: 734-763-5142; E-mail: neovas{at}umich.edu.

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