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FTO regulates ocular angiogenesis via m6A-YTHDF2-dependent mechanism.
Experimental Eye Research ( IF 3.0 ) Pub Date : 2020-06-09 , DOI: 10.1016/j.exer.2020.108107
Kun Shan 1 , Rong-Mei Zhou 1 , Jun Xiang 1 , Ya-Nan Sun 1 , Chang Liu 2 , Meng-Wei Lv 3 , Jian-Jiang Xu 1
Affiliation  

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.



中文翻译:

FTO通过m6A-YTHDF2依赖性机制调节眼血管生成。

病理性眼部血管生成通常会导致视力障碍甚至失明。揭示病理性血管生成的机制对于鉴定调节剂和开发有效的靶向疗法至关重要。在这里,我们使用角膜新生血管(CNV)模型来研究病理性眼部血管新生的机制。我们表明N 6-甲基腺苷(m 6A)由脂肪质量和肥胖相关蛋白(FTO)介导的mRNA去甲基化可以调节CNV期间的内皮细胞(EC)功能和病理性血管生成。在病理条件下,新血管形成的角膜和EC中的FTO水平升高。EC的FTO体外沉默导致在基础和病理条件下细胞增殖,迁移和管形成减少。此外,FTO沉默可在体内减弱缝合线诱导的CNV。从机械上讲,EC中的FTO沉默可以增加关键促血管生成基因(如FAK)中m 6 A的甲基化水平,从而导致RNA稳定性降低,并通过m 6 A阅读器YTHDF2导致RNA衰减增加。我们的研究表明FTO通过控制m的EC功能来调节病理性眼部血管生成6 A-YTHDF2依赖性方式。

更新日期:2020-06-09
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