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on October 2, 2003

Arteriosclerosis, Thrombosis, and Vascular Biology. 2003
Published online before print October 2, 2003, doi: 10.1161/01.ATV.0000098644.03153.6F
A more recent version of this article appeared on November 1, 2003
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Submitted on August 25, 2003
Accepted on August 26, 2003

Vascular Endothelial Growth Factor-Regulated Gene Expression in Endothelial Cells. KDR-Mediated Induction of Egr3 and the Related Nuclear Receptors Nur77, Nurr1, and Nor1

Dan Liu ; Haiyan Jia ; David Ian Roderick Holmes ; Anita Stannard ; and Ian Zachary *

From BHF Laboratories, Department of Medicine, University College London, London, UK.

* To whom correspondence should be addressed. E-mail: I.Zachary{at}ucl.ac.uk.

Objective--The program of gene expression regulated by vascular endothelial growth factor (VEGF) remains poorly understood. The aim of this study was to identify VEGF-regulated genes in human umbilical vein endothelial cells.

Methods and Results--VEGF-regulated gene expression was analyzed by screening Affymetrix oligonucleotide arrays and quantitative, real-time, reverse transcription-polymerase chain reaction. The most strongly induced genes were the NR4A nuclear receptor family members Nur77, Nurr1, and Nor1 and the zinc-finger transcription factor Egr3. VEGF also induced rapid expression of DSCR1, cyclooxygenase-2, tissue factor, stanniocalcin-1, the serine/threonine kinase Cot, and EHD3. VEGF-induced NR4A family and Egr3 expression was blocked by a KDR inhibitor, and prostaglandin F1 and basic fibroblast growth factor weakly increased expression of these genes. Induction of NR4A genes was mediated via intracellular Ca2+, protein kinase C- and calcineurin-dependent pathways. VEGF increased protein expression of Nurr1 and Nur77 and decreased Nur77 phosphorylation at the negative regulatory site serine 351.

Conclusions--VEGF induces expression of NR4A nuclear receptors and Egr3 via KDR and KDR-mediated signaling mechanisms. The genes identified here are novel candidates as key early mediators of VEGF-induced endothelial functions.
Key words: vascular endothelial growth factor • prostaglandin F1 • basic fibroblast growth factor • gene array




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