1. ¹BHF Laboratories, Department of Medicine, University College London, London, UK
2. ²Ark Therapeutics Ltd, Department of Medicine, University College London, London, UK

Correspondence: Professor I Zachary, BHF Laboratories, Department of Medicine, University College London, The Rayne Building, 5 University Street, London WC1E 6JJ, UK. E-mail: I.Zachary@ucl.ac.uk

Received 9 August 2007; Revised 1 November 2007; Accepted 2 November 2007; Published online 3 December 2007.

Abstract

Early growth response 3 (Egr3) is a member of a zinc-finger transcription factor subfamily, which we previously found to be strongly upregulated by vascular endothelial growth factor (VEGF)-A in an oligonucleotide microarray screen of endothelial cells. Here, we show that Egr3 is the predominant Egr family member upregulated by VEGF in endothelial cells at 45 min, and that VEGF induced a rapid increase in Egr-dependent transcriptional activation mediated via its major signalling receptor, VEGFR2/KDR, and the protein kinase C (PKC) pathway. VEGF-induced Egr3 gene expression was also mediated in part via a PKC-dependent activation of protein kinase D. Inhibition of Egr3 gene expression by RNA interference was effective in inhibiting basal and VEGF-induced Egr3 gene expression, and it also inhibited VEGF-mediated endothelial cell proliferation, migration and tubulogenesis. These findings indicate that Egr3 has an essential downstream role in VEGF-mediated endothelial functions leading to angiogenesis and may have particular relevance for adult angiogenic processes involved in vascular repair and neovascular disease.