Targeting ATF6 reduces pathological neovascularization and improves visual outcomes in retinal disease models

Pathological retinal neovascularization is a cause of vision loss in diseases including retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and diabetic retinopathy. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism that is activated by E...

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Bibliographic Details
Published in:Scientific reports Vol. 15; no. 1; pp. 33070 - 15
Main Authors: Bradley, Allyssa, Park, Soyoung, Park, Soyeon, Kim, Kyle, Galdamez, Angela, Min, Hyejung, Diaz-Aguilar, Monica Sophia, Hartnett, M. Elizabeth, Lee, Eun-Jin, Lin, Jonathan H.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 26.09.2025
Nature Publishing Group
Nature Portfolio
Subjects:
631/136/16
631/378/2613/1786
692/699/3161/3175
692/699/3161/3175/3188
Activating transcription factor 6
Activating Transcription Factor 6 - antagonists & inhibitors
Activating Transcription Factor 6 - genetics
Activating Transcription Factor 6 - metabolism
Age
Angiogenesis
Animals
Blood vessels
Cell Proliferation
Diabetes mellitus
Disease Models, Animal
Endothelial cells
Humanities and Social Sciences
Hyperoxia
Hypoxia
Hypoxia-inducible factor 1a
Kinases
Macular degeneration
Mice
Mice, Inbred C57BL
Mice, Knockout
multidisciplinary
Physiology
Postpartum period
Protein folding
Proteins
Retina
Retina - metabolism
Retina - pathology
Retinal Neovascularization - genetics
Retinal Neovascularization - metabolism
Retinal Neovascularization - pathology
Retinopathy
Retinopathy of Prematurity - metabolism
Retinopathy of Prematurity - pathology
Science
Science (multidisciplinary)
Signal Transduction
Therapeutic targets
Unfolded Protein Response - genetics
Vascular endothelial growth factor
Vascularization
Vision
Visual perception
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Summary:Pathological retinal neovascularization is a cause of vision loss in diseases including retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and diabetic retinopathy. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism that is activated by ER stress and upregulates many proteins, including angiogenesis factors like VEGF and HIF-1α. This suggests that UPR genes and pathways may drive retinal angiogenesis. Here, we tested the role of the UPR regulator Activating Transcription Factor 6 (ATF6) in pathological and developmental retinal angiogenesis. We induced pathological retinal neovascularization in Atf6 −/− mice using the oxygen-induced retinopathy (OIR) model and found significantly preserved visual function, accompanied by decreased retinal neovascularization, endothelial cell proliferation, and UPR transcriptional program induction. When we chemically blocked ATF6 signaling by intraocular injection of the small molecule Ceapin-A7, we also saw suppressed retinal expression of UPR genes. Additionally, in postnatal day 7 Atf6 −/− mice when the retinal vasculature is developing in response to physiologic intraocular hypoxia, there was a transient but significant defect in pruning and retinal blood vessel extension. Together, our results demonstrate ATF6’s causal role in developmental and pathological retinal angiogenesis and highlight its potential as a therapeutic target to preserve vision in retinal neovascularization diseases.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-025-15393-y