Differential Roles of Metformin on Retinal Neovascularization and Fibrosis on Experimental Neovascular Age-related Macular Degeneration

Abstract

Purpose : To investigate the effects of metformin on retinal neovascularization and fibrosis in a mouse model of neovascular age-related macular degeneration and its mechanism of action.

Methods : Very low-density lipoprotein receptor knockout (Vldlr^-/-) mice, a neovascular age-related macular degeneration (nAMD) model, were used in this study. Vldlr^-/- mice were administered with metformin at the age of postnatal day (P) 10 for 10 days or P180 for 45 days, respectively. Retinal neovascularization and fibrosis were detected by Western blotting analysis, immunofluorescence staining, hematoxylin-eosin staining and Masson staining. The retinal leakage was examined by fundus fluorescein angiography.

Results : In the neovascularization stage, retinal vascular leakage was significantly reduced in Vldlr^-/- mice treated with metformin compared with those treated with vehicle. Levels of the inflammatory factors including VEGF, VCAM-1 and phosphorylated STAT3 (p-STAT3) were decreased in the retinas of Vldlr^-/- mice treated with metformin. The PI3K/AKT signaling pathway and the P38 signaling pathway were suppressed in the retinas of metformin-treated mice relative to those in the control group. In the fibrosis stage, the fibrotic markers such as collagen I, vimentin and CTGF were upregulated in the retinas of Vldlr^-/- mice treated with metformin compared with those treated with vehicle. Protein levels of the inflammatory factors VEGF, ICAM-1 and p-STAT3 were increased, and PI3K/AKT and P38 signaling were also upregulated in the retinas of metformin-treated Vldlr^-/- mice compared with those in vehicle-treated Vldlr^-/- mice.

Conclusions : Metformin inhibits neovascularization in the early stage while promoting fibrosis in the late stage of nAMD by differentially regulating PI3K/AKT and P38 signaling. These results provide evidence and caveats for the clinical usage of metformin in different stages of nAMD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.