Wang Xin, Liang Xu, Huang Shiya, Wei Mingyan, Xu Yuan, Chen Xiaodong, Miao Yanliang, Zong Rongrong, Lin Xiang, Li Shiying, Liu Zuguo, Chen Qian
Xiamen University affiliated Xiamen Eye Center, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Department of Ophthalmology, Suining Central Hospital, Suining, Sichuan, China.
Front Pharmacol. 2025 Mar 20;16:1547492. doi: 10.3389/fphar.2025.1547492. eCollection 2025.
This study aims to investigate the effects and mechanism of action of metformin on retinal neovascularization and fibrosis in a mouse model of neovascular age-related macular degeneration (nAMD).
Very low-density lipoprotein receptor knockout ( ) mice, a mouse model of nAMD, were used in this study. mice were administered metformin on postnatal day (P) 20 for 20 days (early stage of pathological change) or at 5.5 months of age for 45 days (late stage of pathological change). Retinal leakage was examined by fundus fluorescein angiography (FFA). Retinal neovascularization was assessed by lectin staining. Retinal fibrosis was assessed by Western blotting, immunofluorescence staining, and Masson's trichrome staining.
Retinal vascular leakage and neovascularization were significantly reduced in mice treated with metformin compared to those treated with the vehicle at P40. The protein levels of inflammatory factors and phospho(p)-STAT3 were decreased, and P38 and ERK signaling were suppressed in the retinas of metformin-treated mice relative to those in the control group at P40. Fibrotic markers were upregulated in the retinas of mice treated with metformin compared to those treated with the vehicle at 7 months. Levels of the inflammatory factors and p-STAT3 were increased, and PI3K/AKT, P38, and ERK signaling were upregulated in the retinas of metformin-treated mice compared to those in the control group at 7 months.
Metformin inhibits pathological retinal neovascularization but promotes fibrosis in experimental nAMD. These results provide evidence and highlight important considerations for the clinical use of metformin in different stages of nAMD.
本研究旨在探讨二甲双胍对新生血管性年龄相关性黄斑变性（nAMD）小鼠模型视网膜新生血管形成和纤维化的影响及其作用机制。
本研究使用极低密度脂蛋白受体敲除（ ）小鼠，即nAMD小鼠模型。 小鼠在出生后第20天给予二甲双胍治疗20天（病理变化早期）或在5.5月龄时给予45天（病理变化晚期）。通过眼底荧光血管造影（FFA）检查视网膜渗漏情况。通过凝集素染色评估视网膜新生血管形成。通过蛋白质免疫印迹法、免疫荧光染色和Masson三色染色评估视网膜纤维化。
与在P40时接受赋形剂治疗的小鼠相比，接受二甲双胍治疗的 小鼠视网膜血管渗漏和新生血管形成明显减少。在P40时，与对照组相比，接受二甲双胍治疗的 小鼠视网膜中炎症因子和磷酸化（p）-STAT3的蛋白水平降低，P38和ERK信号通路受到抑制。与在7个月时接受赋形剂治疗的小鼠相比，接受二甲双胍治疗的 小鼠视网膜中纤维化标志物上调。在7个月时，与对照组相比，接受二甲双胍治疗的 小鼠视网膜中炎症因子和p-STAT3水平升高，PI3K/AKT、P38和ERK信号通路上调。
二甲双胍在实验性nAMD中抑制病理性视网膜新生血管形成，但促进纤维化。这些结果为二甲双胍在nAMD不同阶段的临床应用提供了证据，并突出了重要的考虑因素。
