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.
Liu
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D
BHF Laboratories, Department of Medicine, University College London, London, UK.
Evans
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I
Britton
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Zachary
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I
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