Metformin Inhibits Retinal Neovascularization but Promotes Retinal Fibrosis on Experimental Neovascular Age-related Macular Degeneration

Qian Chen ^1* Xin Wang ¹ Xu Liang ¹ Shiya Huang ¹ Mingyan Wei ¹ Xu Yuan ¹ Xiaodong Chen ¹ Yanliang Miao ¹ Rongrong Zong ¹ Xiang Lin ² ShiYing Li ³ Zuguo Liu ¹

• ¹ Eye Institute, Xiamen University, Xiamen, China
• ² Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, China
• ³ Department of Ophthalmology, the First Affiliated Hospital of Xiamen University, Xiamen, China

Purpose: To investigate metformin's effects and mechanism of its action on retinal neovascularization and fibrosis in a mouse model of neovascular age-related macular degeneration (nAMD).: Very low-density lipoprotein receptor knockout (Vldlr -/-) mice, a nAMD mouse model, were used in this study. Vldlr -/-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. Retinal neovascularization was detected by lectin staining. Retina fibrosis was detected by Western blotting, immunofluorescence staining, and Masson's trichrome staining. Results: Retinal vascular leakage and neovascularization were significantly reduced in Vldlr -/-mice treated with metformin compared to those treated with vehicle at P40. The protein levels of inflammatory factors and phospho(p)-STAT3 were decreased, and P38 and ERK signaling were suppressed in the retina of metformin-treated Vldlr - /-mice relative to those in the control group at P40. Fibrotic markers were upregulated in the retina of Vldlr -/-mice treated with metformin compared to those treated with vehicle at seven months. Levels of the inflammatory factors and p-STAT3 were increased, and PI3K/AKT, P38, and ERK signaling were upregulated in the retina of metformin-treated Vldlr -/-mice compared to those in the control group at seven months. Conclusions: Metformin inhibits retinal neovascularization but promotes fibrosis in experimental nAMD. These results provide evidence and caveats for the clinical use of metformin in different stages of nAMD.