Research Paper Volume 15, Issue 1 pp 37—52
Genetic deficiency and pharmacological modulation of RORα regulate laser-induced choroidal neovascularization
- 1 Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- 2 Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL 33458, USA
- 3 BIO5 Institute and Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85719, USA
- 4 Department of Immunology and Microbiology, UF Scripps Biomedical Research, Jupiter, FL 33458, USA
Received: July 20, 2022 Accepted: December 29, 2022 Published: January 10, 2023
https://doi.org/10.18632/aging.204480How to Cite
Copyright: © 2023 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Choroidal neovascularization (CNV) causes acute vision loss in neovascular age-related macular degeneration (AMD). Genetic variations of the nuclear receptor RAR-related orphan receptor alpha (RORα) have been linked with neovascular AMD, yet its specific role in pathological CNV development is not entirely clear. In this study, we showed that Rora was highly expressed in the mouse choroid compared with the retina, and genetic loss of RORα in Staggerer mice (Rorasg/sg) led to increased expression levels of Vegfr2 and Tnfa in the choroid and retinal pigment epithelium (RPE) complex. In a mouse model of laser-induced CNV, RORα expression was highly increased in the choroidal/RPE complex post-laser, and loss of RORα in Rorasg/sg eyes significantly worsened CNV with increased lesion size and vascular leakage, associated with increased levels of VEGFR2 and TNFα proteins. Pharmacological inhibition of RORα also worsened CNV. In addition, both genetic deficiency and inhibition of RORα substantially increased vascular growth in isolated mouse choroidal explants ex vivo. RORα inhibition also promoted angiogenic function of human choroidal endothelial cell culture. Together, our results suggest that RORα negatively regulates pathological CNV development in part by modulating angiogenic response of the choroidal endothelium and inflammatory environment in the choroid/RPE complex.