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Alexander Georg Marneros, Mohammad Dahrouj, Zsolt Ablonczy; Progressive dysfunction of the retinal pigment epithelium and retina due to increased VEGF-A levels. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1189.
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Increased VEGF-A has been implicated in the pathogenesis of choroidal neovascularization (CNV) in neovascular age-related macular degeneration (AMD), while its role in nonexudative AMD is not well defined. Mice with increased VEGF-A develop age-dependent morphological features of both forms of AMD, with an early breakdown of the retinal pigment epithelium (RPE) barrier function and a progressive generalized degeneration of the RPE and subsequently of the photoreceptors that occurs also at sites where no CNV is present. This suggests that an increase in VEGF-A has a direct adverse effect on RPE and photoreceptor function independently of the CNV-promoting proangiogenic effect of VEGF-A. Here, we correlated morphological RPE and retinal abnormalities in mice with increased VEGF-A levels with functional defects in these tissues to provide evidence for a direct role of VEGF-A in the development of age-dependent pathologies as seen in nonexudative AMD.
Eyes of mice with increased VEGF-A were used for morphological and ultrastructural analyses. The morphologic abnormalitites were correlated with functional RPE and retinal defects in these mice using electroretinograms (ERGs), OCT and fundus imaging, fluorescent angiography, rhodopsin measurements, and retinoid profiling.
Here we show that morphological RPE abnormalities and retinal thinning correlate with progressive age-dependent attenuation of visual function with abnormal electroretinograms and reduced retinal rhodopsin levels. Retinoid profiling revealed a progressive reduction of 11-cis and all-trans retinal in the retinae of mice with increased VEGF-A, with a relative accumulation of all-trans retinal, consistent with an impaired retinoid transport between the RPE and photoreceptors due to a VEGF-A-induced RPE barrier breakdown.
These findings provide evidence that increased VEGF-A leads to a progressive RPE and retinal dysfunction that occurs independently of CNV lesion formation. The data support a central role of increased VEGF-A not only in the pathogenesis of neovascular but also of nonexudative AMD.
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