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Azza El-Remessy, Ahmed Shanab, Suraporn Matragoon, Susan Fagan, ; Vascular Protective Effects of Candesartan In Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4538.
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© ARVO (1962-2015); The Authors (2016-present)
Ischemic retinopathy including retinopathy of prematurity (ROP) and diabetic retinopathy is characterized by impaired reparative angiogenesis and accelerated pathological neovascularization. The aim of this study is to examine whether the angiotensin receptor blocker (ARB) candesartan can improve angiogenic response in ROP model by selectively enhancing physiological angiogenesis and inhibiting pathological angiogenesis.
ROP was induced by exposing neonatal mice along with their dam to 70% oxygen (hyperoxia) from postnatal day p7 to p12. The pups were brought back to room air (relative hypoxia) and treated with candesartan (10mg/Kg/day, IP) from p12 to p17 (21% oxygen). Retinal vascular density was assessed by isolectin-B4 staining. Peroxynitrite formation and expression of VEGF, iNOS, eNOS, heamoxygenase-1 (HO-1), were assessed by slot-blot, real-time PCR and Western Blot analyses. Glial Muller activation was assessed using immunohistochemistry.
Candesartan decreased the pathological peripheral neovascularization by 70% and improved physiological revascularization of central retina by 45% compared to untreated pups. Hypoxia-induced significant retinal nitrative stress as indicated by nitrite formation (4.2-fold) and nitrotyrosine formation (4.6-fold). These effects were associated with increases in iNOS (2-fold), eNOS (1.6-fold), VEGF (2-fold) but no change in HO-1expression. Treatment with candesartan during hypoxia (p12-p17) completely abrogated nitrative stress, significantly reduced iNOS expression, stimulated HO-1 expression (5-fold) while maintained VEGF and eNOS expression. In parallel, candesartan induced expression of VEGF, eNOS and HO-1 at the mRNA level. Hypoxia-induced glial activation as indicated by radial GFAP was significantly reduced in candesartan-treated animals. Under normoxia, candesartan treatment stimulated expression of VEGF (1.4-fold), eNOS (2-fold) and HO-1 (3-fold) compared to untreated pups.
Candesartan improved reparative angiogenesis and prevented pathological angiogenesis in ischemic retinopathy model. The results suggest a mechanism that involves reducing oxidative and nitrative stress via modulating iNOS and HO-1 expression without altering VEGF levels.
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