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M. Al–Shabrawey, M. Bartoli, M.A. Behzadian, D. Platt, A. El–Remessy, N.–T. Tsai, R.B. Caldwell; Glial Cell Injury and VEGF Over–Expression Are Blocked by NADPH–Oxidase Inhibition in Ischemic Retinopathy . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1896.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To define the pathogenic role of NADPH oxidase activity in retinal neovascularization during oxygen–induced retinopathy (OIR). We have shown previously that the catalytic subunit of NADPH oxidase gp91phox is upregulated during OIR and that inhibiting NADPH oxidase activity blocks retinal neovascularization. Because ischemic retinopathy begins with glial cell injury and overexpression of VEGF, we evaluated the potential role of NADPH oxidase activity in these alterations. Methods: Experiments were done in the mouse model for OIR in which neonatal mice are maintained in 75% oxygen for 5 days (vaso–obliteration period) followed by 5 days in normoxia (relative ischemia period). Mice were treated with or without the NADPH oxidase inhibitor apocynin (10 mg/kg) during the period of relative ischemia. Expression and cellular sources of gp91phox protein were analyzed by double label immunohistochemical techniques. VEGF protein was analyzed by Western blotting. Results: Colocalization of gp91phox with the glial cell injury marker GFAP and the endothelial marker CD31 showed that gp91phox is expressed in both cell types during the period of relative hypoxia when pathological angiogenesis is occurring. The GFAP localization studies also indicated that pathological angiogenesis is associated with astrocyte and Muller glial cell injury and that apocynin treatment prevents this injury. Western analysis showed a significant increase in VEGF expression during the period of pathological angiogenesis (2.6 + 0.8 fold above control levels). This increase was completely blocked by the apocynin treatment. Conclusions: These data indicate that NADPH oxidase activity is critical for pathological angiogenesis during ischemic retinopathy through induction of glial cell injury and upregulation of VEGF expression. Inhibition of NADPH oxidase activity may offer a new therapeutic strategy for suppressing pathological angiogenesis.
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