on November 16, 2006
Published online before print November 16, 2006, doi: 10.1161/01.ATV.0000252842.57585.df
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Submitted on July 14, 2006
Accepted on October 27, 2006
Vascular Endothelial Growth Factor Receptor 2 Plays a Role in the Activation of Aortic Endothelial Cells by Oxidized Phospholipids
Alejandro Zimman ;
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.
* To whom correspondence should be addressed. 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.