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D.H. Platt, M. Bartoli, T. Lemtalsi, R.B. Caldwell; High glucose increases transcriptional activation of VEGF in bovine retinal endothelial cells via peroxynitrite. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1098.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Increased VEGF expression is associated with retinal neovascularization as seen in proliferative diabetic retinopathy. Work in our laboratory has demonstrated a positive correlation between VEGF expression and the formation of peroxynitrite (ONOO–) in models of diabetic retinopathy and retinal neovascularization. We have recently shown that treatment of microvascular endothelial cells with ONOO– induces increased VEGF expression that is dependent on the activation of the transcription factor, signal transducer and activator of transcription 3 (STAT3). Therefore, we hypothesized that high levels of glucose induce increased VEGF expression in microvascular endothelial cells through ONOO– –mediated activation of STAT3. We tested this by determining the effects of the ONOO– decomposition catalyst FeTPPs on high glucose–induced STAT3 activation and VEGF expression in retinal microvascular endothelial cells. Methods: Cultured bovine retinal endothelial cells (BRE) were stimulated with high glucose (25mM) in the presence and absence of FeTPPs (50µM). Real–time quantitative PCR and western analysis was performed to measure VEGF expression in BRE cells. STAT3 activation was monitored by western analysis of tyrosine phosphorylation. Results: High glucose (25mM) stimulation of BRE cells resulted in STAT3 activation and increased levels of VEGF mRNA within 24 hours. This effect was followed by a significant increase in VEGF protein. FeTPPs significantly inhibited the glucose–induced increases in activation of STAT3 and expression of VEGF. Conclusions: Our results indicate that high glucose stimulates VEGF expression in microvascular retinal endothelial cells via peroxynitrite–mediated activation of STAT3. These results suggest that peroxynitrite may be a target in the prevention of diabetic retinopathy.
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