Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China; Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, China.
Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China; Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, China.
Exp Eye Res. 2021 Dec;213:108810. doi: 10.1016/j.exer.2021.108810. Epub 2021 Oct 29.
Retinal arterial macroaneurysms are characterized by the acquired fusiform or saccular dilatations of the retinal artery. Angiotensin II (Ang II) is a major signal molecule of the renin-angiotensin system, which exerts a range of pathogenic actions that are relevant to retinal vascular abnormalities. We aimed to study the effect of Ang II on retinal vessels and explore its relationship with retinal aneurysmal disease. C57BL/6J male mice were administered Ang II at 1000 ng/kg/min for 28 days, and the mice given saline served as controls. The mice in the treatment group were treated once daily by gastric gavage of candesartan cilexetil (an antagonist of Ang II type 1 (AT1) receptor) at 100 mg/kg/day. The in vivo imaging of murine retinas was performed using fundus photography, optical coherence tomography, fluorescein angiography, and indocyanine green angiography at 7th, 14th, and 28th days of infusion. At the end of the infusion and treatment, the morphological changes were evaluated by histopathological examination and electron microscopy; the levels of related proteins in murine retinas were examined by antibody array and Western blot analyses. We found that Ang II infusion induced aneurysm formation in mice retina, which presented as either solitary aneurysms or retinal arterial beading. The aneurysm formation was often accompanied with vessel leakage. Moreover, Ang II infusion itself may result in increased vascular permeability and ganglion cell and inner plexiform layer thickening. The blockade of AT1 receptors by systemic administration of candesartan cilexetil alleviated the Ang II-induced retinal vasculopathy. The protein level analysis further showed that Ang II upregulated IL-1β, PDGFR-β, and MMP-9 expression, and the expression of IL-1β could be inhibited by AT1 receptor antagonist. Our study provides evidence that Ang II is a crucial factor in retinal aneurysm formation and vessel leakage. It is probably the combined effect of Ang II on vessel inflammatory response, pericyte function, and extracellular matrix remodeling that predisposes the retinal arterial wall to aneurysm formation and blood-retinal barrier breakdown.
视网膜动脉大动脉瘤的特征是视网膜动脉获得性梭形或囊状扩张。血管紧张素 II（Ang II）是肾素-血管紧张素系统的主要信号分子，它发挥一系列致病作用，与视网膜血管异常有关。我们旨在研究 Ang II 对视网膜血管的影响，并探讨其与视网膜动脉瘤疾病的关系。C57BL/6J 雄性小鼠给予 Ang II 1000ng/kg/min 持续 28 天，给予生理盐水的小鼠作为对照。治疗组小鼠每天经胃灌胃坎地沙坦西酯（Ang II 型 1（AT1）受体拮抗剂）100mg/kg 一次。在输注的第 7、14 和 28 天，通过眼底照相、光相干断层扫描、荧光素血管造影和吲哚菁绿血管造影对小鼠视网膜进行体内成像。在输注和治疗结束时，通过组织病理学检查和电子显微镜评估形态学变化；通过抗体阵列和 Western blot 分析检查小鼠视网膜中相关蛋白的水平。我们发现 Ang II 输注诱导小鼠视网膜动脉瘤形成，表现为单个动脉瘤或视网膜动脉串珠样改变。动脉瘤形成常伴有血管渗漏。此外，Ang II 输注本身可能导致血管通透性增加和节细胞和内丛状层增厚。全身给予坎地沙坦西酯阻断 AT1 受体可减轻 Ang II 诱导的视网膜血管病变。蛋白水平分析进一步表明，Ang II 上调了 IL-1β、PDGFR-β 和 MMP-9 的表达，AT1 受体拮抗剂可抑制 IL-1β 的表达。我们的研究提供了证据表明 Ang II 是视网膜动脉瘤形成和血管渗漏的关键因素。可能是 Ang II 对血管炎症反应、周细胞功能和细胞外基质重塑的综合作用，使视网膜动脉壁易于形成动脉瘤和血视网膜屏障破坏。
