Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada; Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montréal, Québec, Canada.
Department of Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Hospital, Université de Montréal, Montréal, Québec, Canada.
Am J Pathol. 2019 Nov;189(11):2340-2356. doi: 10.1016/j.ajpath.2019.07.009. Epub 2019 Aug 17.
Retinopathy of prematurity (ROP) is characterized by an initial retinal avascularization, followed by pathologic neovascularization. Recently, choroidal thinning has also been detected in children formerly diagnosed with ROP; a similar sustained choroidal thinning is observed in ROP models. But the mechanism underlying the lack of choroidal revascularization remains unclear and was investigated in an oxygen-induced retinopathy (OIR) model. In OIR, evidence of senescence was detected, preceded by oxidative stress in the choroid and the retinal pigment epithelium. This was associated with a global reduction of proangiogenic factors, including insulin-like growth factor 1 receptor (Igf1R). Coincidentally, tumor suppressor p53 was highly expressed in the OIR retinae. Curtailing p53 activity resulted in reversal of senescence, normalization of Igf1r expression, and preservation of choroidal integrity. OIR-induced down-regulation of Igf1r was mediated at least partly by miR-let-7b as i) let-7b expression was augmented throughout and beyond the period of oxygen exposure, ii) let-7b directly targeted Igf1r mRNA, and iii) p53 knock-down blunted let-7b expression, restored Igf1r expression, and elicited choroidal revascularization. Finally, restoration of Igf1r expression rescued choroid thickness. Altogether, this study uncovers a significant mechanism for defective choroidal revascularization in OIR, revealing a new role for p53/let-7b/IGF-1R axis in the retina. Future investigations on this (and connected) pathway could further our understanding of other degenerative choroidopathies, such as geographic atrophy.
早产儿视网膜病变（ROP）的特征是初始视网膜无血管化，随后发生病理性新生血管形成。最近，在以前被诊断为 ROP 的儿童中也发现了脉络膜变薄；在 ROP 模型中也观察到类似的持续脉络膜变薄。但是，脉络膜再血管化缺乏的机制尚不清楚，并在氧诱导的视网膜病变（OIR）模型中进行了研究。在 OIR 中，检测到衰老的证据，这先于脉络膜和视网膜色素上皮中的氧化应激。这与包括胰岛素样生长因子 1 受体（Igf1R）在内的促血管生成因子的整体减少有关。巧合的是，p53 肿瘤抑制因子在 OIR 视网膜中高度表达。抑制 p53 活性可导致衰老逆转、Igf1r 表达正常化和脉络膜完整性得以保留。OIR 诱导的 Igf1r 下调至少部分是由 miR-let-7b 介导的，因为 i）let-7b 表达在整个氧暴露期间和之后都增强，ii）let-7b 直接靶向 Igf1r mRNA，iii）p53 敲低可减弱 let-7b 表达，恢复 Igf1r 表达并引发脉络膜再血管化。最后，恢复 Igf1r 表达可挽救脉络膜厚度。总之，这项研究揭示了 OIR 中脉络膜再血管化缺陷的重要机制，揭示了 p53/let-7b/IGF-1R 轴在视网膜中的新作用。对该（和相关）途径的进一步研究可以加深我们对其他退行性脉络膜病变（如地理萎缩）的理解。
