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J. Biol. Chem., Vol. 279, Issue 26, 27088-27097, June 25, 2004

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Activation of Vascular Endothelial Growth Factor Receptor-3 and Its Downstream Signaling Promote Cell Survival under Oxidative Stress^*

Jian Feng Wang, Xuefeng Zhang, and Jerome E. Groopman

From the Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Reactive oxygen species (ROS) mediate cell damage and have been implicated in the pathogenesis of diseases that involve endothelial injury. Cells possess antioxidant systems, including intracellular antioxidants and ROS scavenging enzymes, that control the redox state and prevent cell damage. In addition to intracellular antioxidants, certain growth factor receptors can be activated under oxidative stress and trigger downstream cell survival signaling cascades. Vascular endothelial growth factor receptor-3 (VEGFR-3) is a primary modulator of lymphatic endothelial proliferation and survival. Here, we provide evidence that activation of VEGFR-3 signaling in response to hydrogen peroxide (H₂O₂) promotes endothelial cell survival. Treatment with H₂O₂ induced the tyrosine phosphorylation of VEGFR-3 and its association with the signaling adaptor proteins Shc, growth factor receptor binding protein 2, Sos, p85, SHP-2, and phospholipase C-. Of note, a hereditary lymphoedema-linked mutant of VEGFR-3 was not phosphorylated by H₂O₂ treatment. Isoforms of protein kinase C (PKC), and , were also tyrosine-phosphorylated after H₂O₂ stimulation. However, only the isoform of PKC was required for H₂O₂-induced phosphorylation of VEGFR-3. The tyrosine phosphorylation of VEGFR-3 or isoforms of PKC was completely inhibited by treatment with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, a specific inhibitor for Src family kinases, indicating that Src family kinases are upstream of PKC and VEGFR-3. Furthermore, expression of the wild-type but not the lymphoedema-linked mutant form of VEGFR-3 in porcine artery endothelial cells significantly enhanced the activation of Akt after H₂O₂ stimulation. Consistent with these biochemical changes, we observed that expression and activation of the wild-type but not the mutant form of VEGFR-3 inhibited H₂O₂-induced apoptosis. These studies suggest that VEGFR-3 protects against oxidative damage in endothelial cells, and that patients with hereditary lymphoedema may be susceptible to ROS-induced cell damage.

Received for publication, December 22, 2003 , and in revised form, April 12, 2004.

^* This work was supported in part by NIH Grant R01HL61940 and the Diller-Von Furstenburg Family Foundation. 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: Division of Experimental Medicine, Harvard Institutes of Medicine, Beth Israel Deaconess Medical Center, 4 Blackfan Circle, Boston, MA 02115. E-mail: jgroopma{at}bidmc.harvard.edu.

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