The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis.
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.
BHF Laboratories, Department of Medicine, University College London, London, UK.
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D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D017931:DNA Primers; D051776:Early Growth Response Protein 3 / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D017931:DNA Primers; C079945:EGR3 protein, human; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D051776:Early Growth Response Protein 3; C089212:protein kinase D; D011493:Protein Kinase C