Purpose  Hypoxia-inducible factor (HIF)-1 is a key oxygen sensor and is believed to play a key role in ocular neovascularization (NV) in multiple disorders. The purpose of this study is to determine the role of retinal pigment epithelium (RPE)-derived HIF-1a on ocular NV.
Methods HIF-1a conditional KO mice were generated by crossing the transgenic mice expressing Cre in the RPE with HIF-1a floxed mice and used for generation of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV). HIF-1a KO was confirmed by immunohistochemistry using ocular sections and primary RPE cells from the KO mice. Western blot analysis was used to measure levels of HIF-1a, pro-angiogenic and pro-inflammatory factors. Fundus fluorescein angiography was performed to measure the leakage of CNV and CNV area. Results HIF-1a levels were significantly decreased in the RPE and primary RPE cells from the conditional HIF-1a KO mice. Under normal conditions, the HIF-1a KO mice exhibited no apparent histological or visual functional abnormalities as shown by electroretinogram recording. The HIF-a KO mice with OIR showed no significant differences from Wild-type (Wt) mice in retinal levels of HIF-1a and VEGF and the number of pre-retinal neovascular cells. In the laser-induced CNV model, however, the disruption of HIF-1a in the RPE attenuated the over-expression of VEGF and ICAM-1, reduced retinal vascular leakage and CNV area.
Conclusion RPE-derived HIF-1a plays a key role in CNV. Targeting HIF-1a in the RPE is a promising therapeutic strategy for in CNV in age-related macular degeneration.