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Genetic Deficiency and Pharmacological Modulation of RORα Regulate Laser-Induced Choroidal Neovascularization

01-18-2023

“In this study, we present findings for a protective role of RORα in a mouse laser-induced CNV model of neovascular AMD.”

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BUFFALO, NY- January 18, 2023 – A new research paper was published in Aging (listed as "Aging (Albany NY)" by MEDLINE/PubMed and "Aging-US" by Web of Science) Volume 15, Issue 1, entitled, “Genetic deficiency and pharmacological modulation of RORα regulate laser-induced choroidal neovascularization.”

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 new study, researchers Chi-Hsiu Liu, Felix Yemanyi, Kiran Bora, Neetu Kushwah, Alexandra K. Blomfield, Theodore M. Kamenecka, John Paul SanGiovanni, Ye Sun, Laura A. Solt, and Jing Chen from Harvard Medical School, UF Scripps Biomedical Research and University of Arizona 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. 

“Here, we investigated whether RORα regulates CNV using a mouse model of laser-induced CNV, mimicking the neovascular features of wet AMD. We found that expression of RORα was enriched in the mouse choroid/RPE complex and upregulated in laser-induced CNV.”

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.”

DOI: https://doi.org/10.18632/aging.204480 

Corresponding Author: Jing Chen - jing.chen@childrens.harvard.edu 

Keywords: age-related macular degeneration, angiogenesis, choroidal neovascularization, inflammation, nuclear receptors, RORα, VEGFR2, TNFα

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About Aging-US:

Cancer and aging are two sides of age-related tumorigenesis.

The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population.

The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

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