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Y.–Z. Le, L. Zheng, W. Zheng, Y. Chen, H.P. Gerber, N. Ferrara, J.–X. Ma; RPE–Produced VEGF in Choriocapillaris Function . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1382.
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Geographic atrophy is a "dry" form of age–related macular degeneration (AMD) that causes a severe central vision loss in 3.5% of people over 75 years of age in this country. Experimental and clinical evidence demonstrated that abnormality in the RPE is a prerequisite of choriocapillaris loss, a condition reminiscent of some clinical characteristics of geographic atrophy. However, the pathogenic mechanism of the disease is poorly understood and little is known about its treatment. It has been suggested that the RPE is involved in the development, maintenance, and fenestration of the choriocapillaris through the action of vascular endothelial growth factor (VEGF), but the contribution of the RPE–produced VEGF in choroidal development, stability, fenestration, and diseases has not been determined. As a first step to reveal the function of the RPE–produced VEGF, we decided to disrupt VEGF temporally and spatially in mice and determine the effect of VEGF disruption on structural and function of choriocapillaris.
Conditional VEGF null mice were generated by mating the floxed VEGF mice with the mice expressing Cre recombinase in the RPE at various times. VEGF expression in the RPE was determined by immunohistochemistry (IHC) and Western blot. Choriocapillaris density in the conditional VEGF null mice was determined with light, confocal, and electron microscopy. Retinal integrity in the conditional VEGF null mice was determined by measuring retinal function with electroretinography (ERG) and morphology with light microscopy.
Gene expression analysis suggested that VEGF was disrupted in the RPE of the conditional VEGF null mice. Disruption of VEGF during embryonic day 10–15 (E10–15) resulted in a reduction in choriocapillaris density, scotopic ERG amplitudes, and retinal thickness in the conditional VEGF null mice. Characterization of the mice with post–developmental RPE–specific VEGF disruption is in progress.
Our results suggest that the RPE–produced VEGF is required for choriocapillaris development. Since our inducible RPE–specific Cre mice is capable of regulating gene disruption with variable levels of expression at various time, the temporal and spatial VEGF null mice may provide a model to study pathogenic mechanisms and treatment strategies for geographic atrophy.
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