Endothelial TRPV1 Drives Choroidal Neovascularization in Wet Age-Related Macular Degeneration via NF-κB Signaling.

Abstract

PURPOSE: We investigated the effects of endothelial cell transient receptor potential vanilloid 1 (TRPV1) activation on neovascularization and endothelial cell-microglial crosstalk, aiming to clarify the mechanisms underlying choroidal neovascularization (CNV) in wet age-related macular degeneration (wAMD). METHODS: We performed bioinformatics analysis on transcriptomes of retinal pigment epithelium-choroidal tissues from wAMD patients. Vascular leakage was assessed in laser-induced CNV and TRPV1 knockout (TRPV1-/-) mice using fundus fluorescein angiography, optical coherence tomography, hematoxylin and eosin staining, and isolectin B4 staining. TRPV1 expression in CNV mice was determined via immunofluorescence, western blotting, and quantitative real-time polymerase chain reaction analyses. Angiogenesis and microglial activation were examined via pharmacological intervention, siRNA silencing, and co-culture assays. Physiological TRPV1 agonists were analyzed by public metabolomics datasets. RESULTS: TRPV1 was upregulated in patients with wAMD and mice with laser-induced CNV. TRPV1 activation exacerbated vascular leakage in CNV mice, whereas inhibition or knockout had the opposite effects. In human umbilical vein and retinal microvascular endothelial cells, TRPV1 activation promoted tube formation, with no measurable effects on proliferation or migration. TRPV1 promoted the release of inflammatory factors from endothelial cells by regulating the nuclear factor kappa B (NF-κB) pathway, which in turn induced pro-inflammatory polarization of microglia and the secretion of angiogenic factors from microglia, further facilitating angiogenesis. Moreover, linoleic acid, a physiological ligand of TRPV1, activated the endothelial TRPV1/NF-κB pathway to promote angiogenesis. CONCLUSIONS: Endothelial TRPV1 mediated endothelial dysfunction and microglial activation via NF-κB, thereby promoting CNV, with linoleic acid serving as a key activator. TRPV1 can be considered a potential therapeutic target for treating wAMD.