Impacts of Hypoxia-Inducible Factor-1 Knockout in the Retinal Pigment Epithelium on Choroidal Neovascularization

PURPOSE. Hypoxia-inducible factor (HIF)-1 is a key oxygen sensor and is believed to play an important role in neovascularization (NV). The purpose of this study is to determine the role of retinal pigment epithelium (RPE)-derived HIF-1 alpha on ocular NV. METHODS. Conditional HIF-1 alpha knockout (KO) mice were generated by crossing transgenic mice expressing Cre in the RPE with HIF-1 alpha floxed mice, confirmed by immunohistochemistry, Western blot analysis, and fundus fluorescein angiography. The mice were used for the oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models. RESULTS. HIF-1 alpha levels were significantly decreased in the RPE layer of ocular sections and in primary RPE cells from the HIF-1a KO mice. Under normal conditions, the HIF-1 alpha KO mice exhibited no apparent abnormalities in retinal histology or visual function as shown by light microscopy and electroretinogram recording, respectively. The HIF-1 alpha KO mice with OIR showed no significant difference from the wild-type (WT) mice in retinal levels of HIF-1 alpha and VEGF as well as in the number of preretinal neovascular cells. In the laser-induced CNV model, however, the disruption of HIF-1 alpha in the RPE attenuated the over expression of VEGF and the intercellular adhesion molecule 1 (ICAM-1), and reduced vascular leakage and CNV area. CONCLUSIONS. RPE-derived HIF-1 alpha plays a key role in CNV, but not in ischemia-induced retinal NV. (Invest Ophthalmol Vis Sci. 2012;53:6197-6206) DOI:10.1167/iovs.11-8936