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A.B. El–Remessy, M. Al–Shabrawey, T. Miller, M. Bartoli, T.K. Ali, R.W. Caldwell, R.B. Caldwell; Dual Role of Peroxynitrite in Oxygen–Induced Retinopathy: Oxidation versus Nitration . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3228.
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© ARVO (1962-2015); The Authors (2016-present)
Our studies in vitro have shown that oxidative stress promotes endothelial cell death due to excess formation of peroxynitrite, which blocks VEGF–mediated pro–survival signals due to tyrosine nitration of PI3–kinase’s p85 subunit. Our studies have shown that the action of VEGF in activating VEGFR2, c–Src and FAK and promoting angiogenesis also involves peroxynitrite formation, though tyrosine nitration is not involved. To test whether or not peroxynitrite has a role in retinal endothelial cell survival and growth in vivo, we determined the effects of the peroxynitrite decomposition catalyst FeTTPs and the nitration inhibitor epicatechin on vaso–obliteration and neovascularization in the neonatal mouse model of oxygen–induced retinopathy .
Retinal vaso–obliteration and neovascularization were induced by exposing neonatal mice to 75% oxygen from P7 to P12 followed by normoxia exposure from P12 to P17. Vascular density was determined by morphometric analysis of retinal flatmounts labeled with iso–lectin B4. Akt activation and tyrosine nitration of the PI3 kinase p85 subunit were analyzed by immunoprecipitation and Western blotting. Tyrosine nitration was assessed by slot blot.
Hyperoxia caused vaso–obliteration that was associated with decreased Akt activation, increased p85 tyrosine nitration and lipid peroxidation. Treatments from P7–P12 with FeTTPs (1 mg/Kg/day) or epicatechin (10 mg/Kg/day) restored Akt phosphorylation, blocked tyrosine nitration and inhibited vaso–obliteration. Exposing mice to 75% oxygen as before, followed by 5 days in room air (relative hypoxia) resulted in significant retinal neovascularization, which was blocked by FeTTPs, but not altered by epicatechin.
Taken together, these results demonstrate that peroxynitrite has a critical role in mediating both growth and death of the retinal microvasculature in vivo. Our finding that inhibiting nitration blocks vaso–obliteration, but not neovascularization, indicates that the death signal involves peroxynitrite–mediated nitration, whereas the angiogenic signal does not, but may instead depend on peroxynitrite–mediated oxidation.
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