Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia (Fudan University), Laboratory of Myopia, Chinese Academy of Medical Sciences, China.
The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China; Eye Hospital, Nanjing Medical University, Nanjing, China.
Exp Eye Res. 2020 Aug;197:108107. doi: 10.1016/j.exer.2020.108107. Epub 2020 Jun 9.
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 N-methyladenosine (mA) 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 mA methylation levels in critical pro-angiogenic genes, such as FAK, leading to decreased RNA stability and increased RNA decay through mA reader YTHDF2. Our study demonstrates that FTO regulates pathological ocular angiogenesis by controlling EC function in an mA-YTHDF2-dependent manner.
病理性眼部血管生成通常会导致视力损害甚至失明。揭示病理性血管生成的机制对于鉴定调节因子和开发有效的靶向治疗方法至关重要。在这里，我们使用角膜新生血管化（CNV）模型来研究病理性眼部血管生成的机制。我们发现，肥胖相关蛋白（FTO）介导的 N-甲基腺苷（m6A）mRNA 去甲基化可以调节内皮细胞（EC）功能和 CNV 期间的病理性血管生成。在病理性条件下，新生血管化角膜和 EC 中的 FTO 水平增加。在体外沉默 EC 中的 FTO 会导致细胞在基础和病理性条件下的增殖、迁移和管形成减少。此外，FTO 沉默可减轻体内缝线诱导的 CNV。在机制上，EC 中的 FTO 沉默可增加关键促血管生成基因（如 FAK）中的 mA 甲基化水平，导致 RNA 稳定性降低和 RNA 降解增加，通过 mA 阅读器 YTHDF2 发挥作用。我们的研究表明，FTO 通过以 mA-YTHDF2 依赖的方式控制 EC 功能来调节病理性眼部血管生成。
