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D. Maiti, E. J. Duh; Vascular Endothelial Growth Factor Induces Expression and Activity of the MEF2C Transcription Factor in Retinal Endothelial Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4456.
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Vascular endothelial growth factor is a key regulator of both physiological and pathological angiogenesis. Although much is known about the major upstream signaling pathways mediating VEGF’s effect on endothelial cells, relatively less is known about the transcription factors involved in VEGF’s pro-angiogenic activity. The transcription factor myocyte enhancer factor 2C (MEF2C) is thought to play an important role both in vasculogenesis and angiogenesis during vascular development. In this study, we investigated the regulation of MEF2C by VEGF in human retinal endothelial cells.
Expression of MEF2C in human retinal endothelial cells (HRECs) and human umbilical vein endothelial cells (HUVECs) was assayed by real-time PCR and western blot analysis. In addition, the effect of VEGF on MEF2C promoter activity was assessed using a luciferase reporter assay system. The effect of dominant negative MEF2C on HRECs was assessed using a cell migration assay.
We found that VEGF induces MEF2C gene expression in endothelial cells. VEGF induction of MEF2C expression was completely abrogated by inhibition of the protein kinase C pathway and partially abrogated by inhibition of PKC-ß. In addition to regulating MEF2C expression, VEGF treatment of retinal endothelial cells resulted in activation of upstream signaling regulators of MEF2C (p38 MAP kinase and BMK1/ERK5), as well as in activation of MEF2C phosphorylation. In a luciferase reporter gene assay, VEGF stimulated transcription from a MEF2-dependent promoter in endothelial cells. Transfection of a dominant-negative mutant of MEF2C significantly inhibited VEGF-stimulated endothelial cell migration.
These results implicate VEGF as a key regulator of MEF2C, and suggest that MEF2C may be an important transcription factor mediating VEGF’s pro-angiogenic effects in endothelial cells.
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