Retinal Neovascularization Is Reduced in Mice Lacking P66shc

Abstract

Abstract: : Purpose: Oxydative stress seems to play a role in the pathogenesis of proliferative diabetic retinopathy (PDR) contributing to retinal neovascularization. The lack of the protein p66shc in mice confers a selective resistance to stress-induced oxydative damage strongly reducing intracellular free radical formation. In order to address the role of p66shc in retinal neovascularization we ran experiments on neovessel growth in retinas of mice knocked-out for p66shc (p66shc -/-) with the model of ischemia-induced retinal neovascularization. Methods: Mice p66shc-/- and wild-type (wt) were exposed to 75±1% O2 from the postnatal day 7 (P7) to day 12 (P12) to induce retinopathy of prematurity (ROP). At P12 and at P17 p66shc-/- and wt mice from both ROP and controls (not oxygen-treated) were perfused through the left ventricle with fluorescein isothiocyanate-dextran (2 x 106 molecular weight) 50 mg/ml in PBS. Six animals for each experimental group were investigated. The severity of neovascularization was quantified in flat-mounted retinas dividing each retinal quadrant into three equal parts (clock hours) and each clock hour was scored for the presence of neovascular growths, as tufts, ridges or capillary clumps. Thus, each retina could have a score from 0 to 12. Results: At P12, ROP retinas from p66shc-/- mice showed a reduction of posterior avascular area compared to ROP wt retinas. In addition, the neovascular score of ROP p66shc-/- retinas at P17 was decreased up to 36% compared to that of wt ROP retinas (7.3±1.2 vs 11.3±0.5 neovascular score; p<0.001). Conclusions: These preliminary results show that in mice lacking p66shc retinal neovascularization seems inhibited may be partially trough reduced response to hyperoxia. These findings suggest that blockade of p66 functions could be a potential strategy to decrease neovessel growth induced by ischemia. Further experiments are required to address this issue.

Keywords: retinal neovascularization • oxidation/oxidative or free radical damage • diabetic retinopathy