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M. Labazi, D. M. Marcus, F. Lamoke, R. B. Caldwell, M. Bartoli; Regulation of VEGF Gene Expression by the Transcription Factors STAT3 and STAT1. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3985. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The angiogenic and permeability factor, VEGF, plays a critical role in the pathogenesis of ischemic retinopathies. We have previously shown that the activation of the transcription factor STAT3 is necessary for ischemia-induced VEGF up-regulation. We wanted further elucidate the specific role of STAT3 in hypoxia-induced VEGF expression.
Retinal endothelial cells (REC) and human umbilical vein endothelial cells (HUVEC) in culture were subjected to 2% oxygen levels for different times (1h, 3h). Chromatin immunoprecipitation (ChIP) was conducted to identify STAT3 binding to VEGF promoter in hypoxic and normoxic (pO2=23%) condition. Selective inhibition of STAT3 was achieved by siRNA or over-expression of the inactive mutants STAT3F and STAT3D. Western blotting analysis was used to determine phosphoprotein levels.
Hypoxia rapidly stimulated tyrosine phosphorylation (PYSTAT3) and nuclear translocation of STAT3 (1h). Selective inhibition of STAT3 activity significantly blunted hypoxia-induced VEGF expression. Analysis of the VEGF promoter region using ChIP assay revealed that STAT3 binds VEGF promoter in hypoxic conditions in both REC and HUVEC. Of interest, we found that STAT1, which has been reported to have anti-angiogenic activity, binds VEGF promoter in normoxic conditions but not in hypoxia
These data demonstrate that STAT3 is a transcriptional activator of VEGF expression in hypoxic conditions in REC and HUVEC. In addition, our results suggest that STAT1 may function as a repressor of VEGF gene expression in physiological conditions.
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