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Arterioscler Thromb Vasc Biol. 2003 Nov 1;23(11):2002-7. Epub 2003 Oct 2.

Vascular endothelial growth factor-regulated gene expression in endothelial cells: KDR-mediated induction of Egr3 and the related nuclear receptors Nur77, Nurr1, and Nor1.

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  • 1BHF Laboratories, Department of Medicine, University College London, London, UK.

Abstract

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 Down syndrome candidate region 1, cyclooxygenase-2, tissue factor, stanniocalcin-1, the serine/threonine kinase Cot, and eps15 homology domain-containing protein. VEGF-induced NR4A family and Egr3 expression was blocked by a KDR inhibitor, and placental growth factor 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.

PMID:
14525795
[PubMed - indexed for MEDLINE]
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