Loss of Farnesoid X Receptor Signaling Promotes Choroidal Neovascularization in Mice

Abstract

Choroidal neovascularization (CNV) is a defining feature of neovascular age-related macular degeneration (nAMD). Although anti-vascular endothelial growth factor (VEGF) therapies suppress neovascular activity, incomplete responses, recurrent leakage, and subretinal fibrosis remain important clinical challenges. The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor with anti-inflammatory, anti-fibrotic, and anti-angiogenic functions in other tissues, but its role in CNV is unknown. Analysis of publicly available human transcriptomic data (GSE135092) showed FXR expression in the retinal pigment epithelium (RPE)/choroid and significant downregulation in AMD-affected macular RPE/choroid. To define the role of FXR in CNV, laser photocoagulation was performed in wild-type (WT) and FXR-deficient (FXR-KO) mice, with disease progression assessed by in vivo imaging, histology, ex vivo choroidal sprouting, and endothelial cell assays. FXR expression in the RPE/choroid was reduced 14 days after laser injury. Compared with WT mice, FXR-KO mice developed larger CNV lesions, more extensive hyperfluorescence on fluorescein angiography, and increased lesion area during disease progression. FXR deficiency also impaired resolution of fibrotic remodeling. In WT mice, alpha-SMA peaked at day 14 and declined by day 21, whereas collagen I remained low throughout; in FXR-KO mice, both collagen I and alpha-SMA were significantly elevated relative to WT and remained significantly higher than WT at day 21. Consistent with these findings, FXR-deficient choroidal explants exhibited increased vascular sprouting, and FXR-KO endothelial cells formed more extensive capillary-like networks. Together, these findings identify FXR as an endogenous regulator of pathological angiogenesis, vascular leakage, mesenchymal activation, and fibrotic remodeling during CNV and provide a rationale for investigating FXR-directed strategies for nAMD.