FTO regulates ocular angiogenesis via m6 A-YTHDF2-dependent mechanism

Experimental Eye Research
Kun ShanJian-Jiang Xu

Abstract

Pathological ocular angiogenesis commonly results in visual impairment or even blindness. Unveiling the mechanisms of pathological angiogenesis is critical to identify the regulators and develop effective targeted therapies. Here, we used corneal neovascularization (CNV) model to investigate the mechanism of pathological ocular angiogenesis. We show that N6-methyladenosine (m6A) mRNA demethylation mediated by fat mass- and obesity-associated protein (FTO) could regulate endothelial cell (EC) function and pathological angiogenesis during CNV. FTO levels are increased in neovascularized corneas and ECs under pathological conditions. In vitro silencing of FTO in ECs results in reduced cellular proliferation, migration, and tube formation under both basal and pathological conditions. Furthermore, FTO silencing attenuates suture-induced CNV in vivo. Mechanically, FTO silencing in ECs could increase m6A methylation levels in critical pro-angiogenic genes, such as FAK, leading to decreased RNA stability and increased RNA decay through m6A reader YTHDF2. Our study demonstrates that FTO regulates pathological ocular angiogenesis by controlling EC function in an m6A-YTHDF2-dependent manner.

Citations

May 13, 2021·Experimental Eye Research·Nidhi KumariSenthil Kumar Ganesan
Jun 8, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Ying QiQingqing Cui
Jul 3, 2021·International Journal of Molecular Sciences·Vilbert SikorskiEsko Kankuri
Aug 1, 2021·Molecular Biology Reports·Jing-Fan Gao, Lu Zhang
Nov 6, 2021·Frontiers in Immunology·Fangzhou TengJingcheng Dong

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