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C. A. Lange, F. M. Mowat, U. F. O. Luhmann, A. J. Smith, P. H. Maxwell, R. R. Ali, J. W. Bainbridge; Von Hippel-Lindau Expression in the Retinal Pigment Epithelium is Essential for Normal Eye Development and Vascular Homeostasis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5973.
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The retinal pigment epithelium (RPE) is vital for normal ocular development and photoreceptor function and maintains the outer blood-retinal barrier. This study aimed to investigate the role of the von Hippel-Lindau tumor suppressor protein (pVHL) in the RPE.
We generated mice with conditional inactivation of pVHL in the RPE (VHLrpe-/- mice) by breeding VHL floxed mice with transgenic mice that express cre-recombinase under the control of the RPE-specific promoter tyrosinase related protein 1. We measured the axial length, the histological phenotype and retinal function by electrophysiology in VHLrpe-/- mice and in control littermates at timepoints during postnatal development. We investigated the effect of RPE specific inactivation of pVHL on the hypoxia inducible factor 1 (HIF-1) pathway by immunohistochemistry, and the effects on the ocular vasculature by FITC-perfused retinal and choroidal flatmounts, and Collagen4-stained cryosections.
Eyes of VHLrpe-/- mice were severely micro-ophthalmic from postnatal day (P) 0 and developed to a maximal axial length of 2.1mm compared with 3.1mm in control mice at P31. Histological examination revealed severe iris (P0) and cilliary body defects (P7), outer retinal retinal rosette formation (P7) and a complete retinal degeneration with no detectable response on electroretinography in adult mice. Immunohistochemical analysis demonstrated stabilization of HIF-1alpha in the RPE, disordered retinal vascular beds and the formation of chorio-retinal anastomoses as well as corneal neovascularisation from P7 onwards.
RPE specific pVHL is critical for normal ocular growth and vascular development. The postnatal development of abnormal corneal, retinal and choroidal vascular beds is consistent with constitutive activation of the HIF pathway and consequent overexpression of pro-angiogenic factors. Whether microphthalmia, retinal rosette formation and retinal dysfunction is also a direct or indirect consequence of HIF stabilisation, or the result of other pVHL target molecules, is the subject of further investigation.
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