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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:332.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Vascular Endothelial Growth Factor Receptor 2 Plays a Role in the Activation of Aortic Endothelial Cells by Oxidized Phospholipids

Alejandro Zimman; Kevin P. Mouillesseaux; Thang Le; Nima M. Gharavi; Ann Ryvkin; Thomas G. Graeber; Tom T. Chen; Andrew D. Watson; Judith A. Berliner

From the Departments of Medicine (A.Z., K.P.M., T.L., N.M.G., J.A.B.), Pathology (A.Z., K.P.M., T.L., N.M.G., J.A.B.), Molecular & Medical Pharmacology (A.R., T.G.G.), Crump Institute for Molecular Imaging (T.G.G.), Cardiology (A.D.W.), and the Molecular Biology Institute (T.T.C.), University of California, Los Angeles.

Correspondence to Judith A. Berliner, 13-229 CHS, 650 Charles Young South, Los Angeles, CA 90095-1732. E-mail jberliner{at}mednet.ucla.edu

Objective— Previous studies have shown that oxidized products of PAPC (Ox-PAPC) regulate cell transcription of interleukin-8, LDL receptor, and tissue factor. This upregulation takes place in part through the activation of sterol regulatory element-binding protein (SREBP) and Erk 1/2. The present studies identify vascular endothelial growth factor receptor 2 (VEGFR2) as a major regulator in the activation of SREBP and Erk 1/2 in endothelial cells activated by Ox-PAPC.

Methods and Results— Ox-PAPC induced the phosphorylation of VEGFR2 at Tyr¹¹⁷⁵ in human aortic endothelial cells. Inhibitors and siRNA for VEGFR2 decreased the transcription of interleukin-8, LDL receptor, and tissue factor in response to Ox-PAPC and the activation of SREBP and Erk 1/2, which mediate this transcription. We provide evidence that the activation of VEGFR2 is rapid, sustained, and c-Src–dependent.

Conclusions— These data point to a major role of VEGFR2 in endothelial regulation by oxidized phospholipids which accumulate in atherosclerotic lesions and apoptotic cells.

We identified VEGFR2 as a regulator of the transcription of IL-8, LDL-R, and TF induced by Ox-PAPC in human aortic endothelial cells. The activation of VEGFR2 is rapid, sustained, and depends on the activation of c-Src kinase.

Key Words: oxidized phospholipids • VEGFR2 • atherosclerosis • endothelium

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				S. Lee, R. Li, B. Kim, R. Palvolgyi, T. Ho, Q.-Z. Yang, J. Xu, W. L. Szeto, H. Honda, and J. A. Berliner Ox-PAPC activation of PMET system increases expression of heme oxygenase-1 in human aortic endothelial cell J. Lipid Res., February 1, 2009; 50(2): 265 - 274. [Abstract] [Full Text] [PDF]