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Toshihide Kurihara, Yoshihiko Usui, Edith Aguilar, Daniel Feitelberg, Carli M Wittgrove, Peter D Westenskow, Martin Friedlander; Neuronal VHL Deletion Induces Strong Suppression of Retinal Vascular Formation. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5371.
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von Hippel-Lindau protein (VHL) and its target hypoxia-inducible factors (HIFs) play important roles in the development, physiology, and pathophysiology of many tissues. In general, HIF stabilization and activation (caused by VHL deletion) induces pro-angiogenic gene expression. Previously, we have reported activities of VHL and HIF in neurons, astrocyte, myeloid cells, and pigment epithelium cells during development and maturation of the retina (Development. 2010, J Cell Biol. 2011, J Clin Invest. 2012). However, the role of VHL in vascular development is still not well understood. In this study, retinal vascular development regulated by neuronal VHL was investigated utilizing retinal pan-neuronal conditional knockout mice.
CRX-Cre mice were crossed with ROSA26-GFP reporter mice to confirm the expression of cre recombinase. Retinal neuronal specific conditional VHL knockout mice were obtained by crossing CRX-Cre mice with VHLfloxed/floxed mice (VHL;CRX-Cre mice). Fundus photography, immunohistochemistry, histology, and electrophysiology were used to examine the phenotype of these mice.
CRX-Cre;ROSA26 mice expressed GFP in all neurons throughout the entire retina. Surprisingly, VHL:CRX-Cre mice revealed an arrest of retinal vascular development despite strong HIF stabilization in these cells. On the other hand, VHL:CRX-Cre mice showed proliferative hyaloidal vascular endothelial cells on the surface of the retina as well as photoreceptor degeneration. These phenotypes resemble persistent fetal vasculature (PFV) observed in developmental human retinal disease.
These data suggest that neuronal VHL is critical for proper vascular and neuronal development in the retina. The VHL-HIF cascade could be targeted to prevent or treat retinal developmental anomalies such as PFV.
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