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A.B. El–Remessy, M. Al–Shabrawey, N. Ghaly, D.H. Platt, M. Bartoli, M. Behzadian, K. Motamed, R.B. Caldwell; Role of Peroxynitrite in Retinal Neovascularization and VEGF Angiogenic Signaling . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4200.
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Purpose: Peroxynitrite is a powerful reactive nitrogen species that causes oxidation of protein–associated thiol groups and nitration of tyrosine residues. We have shown that high levels of peroxynitrite (0.5 mM) inactivate VEGF survival signaling and accelerate endothelial cell death. This effect is associated with significant tyrosine nitration of the p85 subunit of PI3–kinase and decreases in Akt kinase activity. We have shown also that low levels of peroxynitrite (1 µM) do not cause tyrosine nitration, but mimic the effects of VEGF in causing immediate tyrosine phosphorylation of VEGFR2, c–Src and focal adhesion kinase (FAK) which are known to be involved in VEGF’s angiogenic function. The purpose of this study was to test the specific role of peroxynitrite–induced tyrosine nitration in retinal neovascularization in vivo and VEGF–induced angiogenic function in vitro. Methods: Studies were done to compare the effects of the specific peroxynitrite decomposition catalyst (FeTPPs) and the specific nitration inhibitor (epicatechin) on retinal neovascularization in the mouse model for oxygen–induced retinopathy (OIR) and on VEGF–mediated–angiogenic function and signalling in retinal endothelial cells in vitro. Results: Treatment of OIR mice with FeTPPs (1 mg/kg/day) during the period of relative retinal hypoxia significantly reduced retinal neovascularization, whereas epicatechin (10 mg/kg/day) had little effect. In vitro assays showed that FeTPPs (2.5 µM) also blocked the action of VEGF (30 ng/ml) in stimulating cell proliferation, migration and alignment into tube–like structures, whereas epicatechin (100 µM) had no significant effect. FeTPPs (2.5 µM) also blocked the actions of both VEGF and exogenous peroxynitrite (1 µM) in stimulating tyrosine phosphorylation of VEGFR2, cSrc and FAK, whereas epicatechin enhanced these effects. Conclusions:Taken together, these results indicate a novel role of peroxynitrite in mediating retinal neovascularization. Moreover, the data showing enhancement of VEGF–induced tyrosine phosphorylation by epicatechin indicate that peroxynitrite–mediated tyrosine nitration is not a key player in mediating VEGF’s angiogenic signal and imply a role for peroxynitrite–mediated oxidation in this process. Treatments targeting peroxynitrite may be effective in anti–angiogenic therapy.
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