Targeting ATF6 Reduces Pathological Neovascularization and Improves Visual Outcomes in Retinal Disease Models

Pathological retinal neovascularization is a common mechanism for leading causes of vision loss including retinopathy of prematurity (ROP), diabetic retinopathy, and wet age-related macular degeneration. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism controlled by the ER-resident proteins ATF6, IRE1, and PERK. In response to endoplasmic reticulum stress, UPR activates downstream transcriptional and translational programs that upregulate many proteins, including key angiogenesis factors like VEGF and HIF1a. This suggests an important role for UPR in developmental and pathologic retinal angiogenesis, but it is unclear which UPR regulatory genes are most important in these processes. Here, we focused on the role of Activating Transcription Factor 6 (ATF6) in pathologic and developmental retinal angiogenesis. We induced pathologic retinal neovascularization in Atf6-/- mice using the oxygen-induced retinopathy (OIR) model of ROP and examined functional, histologic, and molecular consequences in the retina. we found significantly preserved visual function, accompanied by decreased retinal neovascularization, endothelial cell proliferation, and UPR and angiogenesis transcriptional programs in Atf6-/- mice after OIR. When we chemically blocked ATF6 signaling by intraocular injection of the small molecule Ceapin-A7, we also saw suppression of UPR and angiogenesis gene expression. Last, we examined very young Atf6-/- mice when the inner retinal vasculature is developing and found a significant defect in pruning and blood vessel extension to the periphery at P7, but this delay was transient and Atf6-/- blood vessels fully recovered at older ages of development. Together, our results demonstrate ATF6's critical role in developmental and pathological angiogenesis and highlight its potential as a therapeutic target to mitigate pathological retinal neovascularization. Overall design: RNA-seq profiling of Atf6-/- mouse retinas (C57BL/6J background) subjected to oxygen-induced retinopathy model of Retinopathy of Prematurity and wildtype mouse retinas subjected to intraocular injection of Atf6 inhibitor Ceapin-A7