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Liliana Paris, Toshihide Kurihara, Peter Westenskow, Stephen Bravo, Carli Wittgrove, Edith Aguilar, Martin Friedlander; RPE-specific VEGF Deletion Induces Geographic Atrophy: a Long-term Study. Invest. Ophthalmol. Vis. Sci. 2013;54(15):365.
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Photoreceptor atrophy occurs in human patients with geographic atrophy (GA) associated with dysfunction or death of retinal pigment epithelial (RPE) cells. We have shown that inducible RPE-specific vascular endothelial growth factor (VEGF) conditional deletion in adult mice induces atrophy of the choriocapillaris and cone photoreceptor dysfunction within days post-induction (Kurihara T et al. J Clin Invest. 2012). Surprisingly, no noticeable defects were observed in rod photoreceptors as late as 7 months post induction. In this study we report observations up to 11 months after VEGF deletion in RPE cells
Mice harboring floxed Vegfa alleles and RPE-specific inducible Cre transgenes (VMD2-Cre) were crossed to generate Vegfafl/fl;VMD2-Cre, these were injected intraperitoneally with doxycycline at 6-8 weeks of age. Electron microscopy, confocal scanning laser ophthalmoscopy (cSLO), indocyanine green angiography (ICG) and optical coherence tomography (OCT) were performed as early as 5 months post induction to detect and quantify morphological changes in RPE cells, photoreceptors and the vasculature.
The absence of the choriocapillaris was consistently observed at all stages examined. Five months after induction, the basal infoldings of the mutant RPE cells become disorganized and large vacuoles appear, increasing over time. At 9 months post-induction, lipid droplets, subretinal deposits, photoreceptor and RPE atrophy were observed. cSLO revealed hyperautofluorescence after 9 months and dilated retinal vessels were observed using ICG and OCT 11 months post induction. None of these defects were observed at any stage in age-matched control mice
Atrophy of the choriocapillaris is observed 3 days post-induction and is not reversed as late as 11 months post-induction. Rod photoreceptor and RPE atrophy in the VEGF mutants is observed by 9 months post-induction and its late onset resembles that observed in human GA. Choriocapillaris thinning has previously been described in aging human eyes and may induce hypoxia in RPE cells. The findings of this study suggest the hypoxic RPE environment may contribute to GA development
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