Ceapin‐A7 Suppresses UPR Signaling and Mitigates Retinal Neovascularization in Vldlr−/− Mice

Abstract

Pathological neovascularization drives blinding retinal diseases, including diabetic retinopathy, retinopathy of prematurity, and neovascular age‐related macular degeneration. Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling are key mechanisms underlying neovascularization. Mice lacking the UPR regulator Activating Transcription Factor 6 (ATF6) show normal retinal vasculature yet are resistant to pathologic neovascularization, suggesting that ATF6 inhibition may mitigate retinal damage and vision loss from aberrant retinal angiogenesis. We tested Ceapin‐A7, a selective ATF6 inhibitor, in Vldlr−/− mice, a genetic model of retinal neovascularization. Intravitreal Ceapin‐A7 reduced ectopic vascular projections into the outer retina and significantly increased scotopic b‐wave amplitude, while a‐wave and photopic responses showed no significant difference between groups. Single‐nucleus RNA sequencing revealed suppressed ATF6/UPR gene programs and angiogenic pathways in retinal endothelial cells and reduced Müller cell gliosis. These findings demonstrate that pharmacologic ATF6 inhibition mitigates retinal neovascularization in Vldlr−/− mice and identifies ATF6/UPR as a therapeutic target for neovascular retinal diseases.