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
Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA.
Department of Ophthalmology, School of Medicine, Stanford University, Palo Alto, CA, USA.
Sci Rep. 2025 Sep 26;15(1):33070. doi: 10.1038/s41598-025-15393-y.
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.
病理性视网膜新生血管形成是导致包括早产儿视网膜病变（ROP）、湿性年龄相关性黄斑变性（AMD）和糖尿病性视网膜病变在内的多种疾病视力丧失的原因。未折叠蛋白反应（UPR）是一种细胞内信号转导机制，由内质网应激激活，并上调许多蛋白质，包括血管生成因子如血管内皮生长因子（VEGF）和缺氧诱导因子-1α（HIF-1α）。这表明UPR基因和信号通路可能驱动视网膜血管生成。在此，我们测试了UPR调节因子激活转录因子6（ATF6）在病理性和发育性视网膜血管生成中的作用。我们使用氧诱导视网膜病变（OIR）模型在Atf6基因敲除小鼠中诱导病理性视网膜新生血管形成，发现视觉功能显著保留，同时视网膜新生血管形成、内皮细胞增殖和UPR转录程序诱导减少。当我们通过眼内注射小分子Ceapin-A7化学阻断ATF6信号时，我们还观察到UPR基因的视网膜表达受到抑制。此外，在出生后第7天的Atf6基因敲除小鼠中，当视网膜血管系统因生理性眼内缺氧而发育时，在修剪和视网膜血管延伸方面存在短暂但显著的缺陷。总之，我们的结果证明了ATF6在发育性和病理性视网膜血管生成中的因果作用，并突出了其作为治疗靶点以保护视网膜新生血管疾病视力的潜力。
