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Chi-Hsiu Liu, Shuo Huang, Zhongxiao Wang, William Britton, Ye Sun, Jing Chen; RORα Regulates Experimental Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4344.
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Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. Choroidal neovascularization (CNV) leads to the majority of AMD-related blindness. Dysregulation of lipid-cholesterol metabolic pathways is implicated in CNV formation. Retinoic acid receptor-related orphan receptor alpha (RORα), a lipid-sensing nuclear receptor, is linked with AMD genetically. RORα functions as a ligand (cholesterol derivatives)-dependent transcriptional regulator and mediates gene expression in many physiological processes, including lipid metabolism and immunity. Here we investigated the role of RORα in the regulation of CNV using a laser-induced mouse model.
Laser photocoagulation was performed to induce CNV in mice with spontaneous RORα deficiency (RoraSg/Sg), the littermate wild type (WT) controls, macrophage-specific RORα knockout (LysMCre; Roraf/f), and Roraf/f. CNV lesion size and leakage were analyzed with in vivo fluorescein fundus angiography (FFA) evaluation and in isolated choroid complex flat mounts and cross-sections from enucleated eyes stained with vascular markers. Expression levels of Rora and relevant angiogenic, metabolic and inflammatory genes were analyzed in retinas and RPE/choroid complexes from mouse eyes with induced CNV.
RORα is expressed in both retinas and RPE/choroid complexes in WT eyes, with specific staining in macrophages. Genetic deficiency of RORα significantly increases CNV lesion size in RPE/choroidal flat mounts, with increased recruitment of macrophages to CNV lesions. CNV vessel leakage is also worsened with RORα deficiency as analyzed by FFA imaging. Moreover, macrophage-specific knockout of RORa (LysMCre; Roraf/f) leads to significantly larger CNV lesion areas, suggesting a negative role of RORα in regulating macrophage activity and CNV formation. Upregulation of pro-angiogenic, pro-inflammatory, and other immune-related genes are found in RORα deficient choroidal complex with induced CNV, consistent with increased CNV lesion size in the absence of RORα.
Our findings suggest that both systemic and macrophage deficiency of RORα worsens CNV, and indicate that RORα may be a new molecular target for inhibiting CNV in neovascular AMD.
This is a 2020 ARVO Annual Meeting abstract.
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