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Updated: Aug 14, 2025
A Mouse Model for Laser-induced Choroidal Neovascularization
Published on: December 27, 2015
Genetic deficiency and pharmacological modulation of RORα regulate laser-induced choroidal neovascularization
Chi-Hsiu Liu1, Felix Yemanyi1, Kiran Bora1
1Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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.
Insights
Nuclear receptor RORα (RAR-related orphan receptor alpha) negatively regulates choroidal neovascularization (CNV) in age-related macular degeneration (AMD). Loss of RORα exacerbates CNV, while its inhibition promotes blood vessel growth.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Choroidal neovascularization (CNV) is a major cause of vision loss in neovascular age-related macular degeneration (AMD).
- The role of the nuclear receptor RAR-related orphan receptor alpha (RORα) in pathological CNV is not fully understood, despite genetic links to AMD.
Purpose of the Study:
- To investigate the specific role of RORα in the development of pathological CNV.
- To determine how RORα influences angiogenic and inflammatory pathways in the choroid and retinal pigment epithelium (RPE).
Main Methods:
- Analysis of RORα expression in mouse choroid and RPE.
- Utilizing Staggerer mice (Rorasg/sg) with genetic RORα deficiency in a laser-induced CNV model.
- Assessing CNV lesion size, vascular leakage, and protein levels of VEGFR2 and TNFα.
- Investigating the effects of RORα inhibition on isolated mouse choroidal explants and human choroidal endothelial cells.
Main Results:
- RORα is highly expressed in the mouse choroid and its expression increases post-laser CNV induction.
- Genetic loss or pharmacological inhibition of RORα significantly worsened CNV, increasing lesion size and vascular leakage.
- RORα deficiency or inhibition led to increased VEGFR2 and TNFα levels and promoted vascular growth in vitro and ex vivo.
Conclusions:
- RORα acts as a negative regulator of pathological CNV.
- RORα's protective effect is mediated by modulating choroidal endothelial cell angiogenesis and the inflammatory environment in the choroid/RPE complex.
