Soluble very low‐density lipoprotein receptor (sVLDLR) inhibits fibrosis in neovascular age‐related macular degeneration

Subretinal fibrosis is a key pathological feature in neovascular age‐related macular degeneration (nAMD). Previously, we identified soluble very low‐density lipoprotein receptor (sVLDLR) as an endogenous Wnt signaling inhibitor. This study investigates whether sVLDLR plays an anti‐fibrogenic role in nAMD models, including Vldlr (−/−) mice and laser‐induced choroidal neovascularization (CNV). We found that fibrosis factors including P‐Smad2/3, α‐SMA, and CTGF were upregulated in the subretinal area of Vldlr (−/−) mice and the laser‐induced CNV model. The antibody blocking Wnt co‐receptor LRP6 significantly attenuated the overexpression of fibrotic factors in these two models. Moreover, there was a significant reduction of sVLDLR in the interphotoreceptor matrix (IPM) in the laser‐induced CNV model. A transgenic strain (sVLDLR‐Tg) with sVLDLR overexpression in the IPM was generated. Overexpression of sVLDLR ameliorated the profibrotic changes in the subretinal area of the laser‐induced CNV model. In addition, Wnt and TGF‐β signaling synergistically promoted fibrogenesis in human primary retinal pigment epithelium (RPE) cells. CRISPR/Cas9‐mediated LRP6 gene knockout (KO) attenuated this synergistic effect. The disruption of VLDLR expression promoted, while the overexpression of sVLDLR inhibited TGF‐β‐induced fibrosis. These findings suggest that overactivated Wnt signaling enhances the TGF‐β pathway in subretinal fibrosis. sVLDLR confers an antifibrotic effect, at least partially, through the inhibition of Wnt signaling and thus, has therapeutic potential for fibrosis.