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Edith Aguilar, Toshihide Kurihara, Yoshihiko Usui, Peter D Westenskow, Carli M Wittgrove, Martin Friedlander; Hypoxia-inducible factors in retinal pigment epithelium cell regulate pathological phenotypes in a murine model of macular telangiectasia, the VLDLR knockout mouse. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5401.
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During hypoxia, inflammation, and aging, hypoxia-inducible factor-αs (HIF-1α and Hif-2α) play important roles in maintaining cell function and viability. Retinal pigment epithelium (RPE) dysfunction or cell death can lead to age-related macular degeneration, although little is known about the contribution of the RPE in macular telangiectasia (MacTel). In this study we utilized inducible RPE-specific knockout technology to determine the precise in vivo functions of HIF-αs in a murine model of MacTel, the very low density lipoprotein receptor knockout (VLDLR-/-) mouse.
Doxycycline injections in adult VMD2-Cre mice induced Cre-mediated recombination specifically in RPE cells. VMD2-Cre mice were crossed with HIF-1α flox/flox, HIF-2α flox/flox mice and/or VEGFflox/flox to obtain RPE specific knockouts. These mice were further crossed with VLDLR-/- mice to examine the contribution of HIF-αs and VEGF to the neovascular and atrophic changes observed in the VLDLR-/- mouse. Mice were examined using immunohistochemistry, and electroretinography.
VEGF deletion in RPE of VLDLR-/- mice rescued the neovascular phenotype, but exacerbated the atrophy. In contrast, HIF-2α deletion rescued both neovascular and atrophic phenotypes in VLDLR-/- mice. Lastly, HIF-1α deletion rescued the neovascular phenotype and did not affect the atrophy.
In this study, we found that HIF-αs in RPE cells contribute significantly to the progression of the neovascular and atrophic phenotypes in VLDLR-/- mice. These results suggest that RPE-derived HIF-αs can be therapeutic targets in the treatment of MacTel and similar types of retinal degeneration.
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