Zuo Hangjia, Liu Xianyang, Wang Yakun, Ding Huannan, Wan Wenjuan, Zheng Shijie, Hou Shengping, Hu Ke
The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, PR China; Chongqing Medical University, Chongqing, PR China.
The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, PR China; Chongqing Medical University, Chongqing, PR China; Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, 100730, China.
Exp Eye Res. 2025 Mar;252:110239. doi: 10.1016/j.exer.2025.110239. Epub 2025 Jan 10.
Retinopathy of prematurity (ROP) is a proliferative retinal vascular disorder that critically affects the visual development of premature infants, potentially leading to irreversible vision loss or even blindness. Despite its significance, the underlying mechanisms of this disease remain insufficiently understood. In this study, we utilized the oxygen-induced retinopathy (OIR) mouse model and conducted endothelial functional assays to explore the role of Sterol Regulatory Element-Binding Protein 1 (SREBF1) in ROP pathogenesis. SREBF1 expression levels, along with its downstream targets, were investigated through Western blotting, RT-qPCR, and immunofluorescence staining techniques. Furthermore, Co-Immunoprecipitation (Co-IP) was employed to examine the molecular mechanisms involved. Our results demonstrated a significant increase in SREBF1 expression in both the OIR mouse model and hypoxic primary human retinal microvascular endothelial cells (HRMECs). Interventions conducted both in vivo and in vitro showed notable efficacy in reducing pathological neovascularization. Importantly, we discovered that SREBF1 plays a key role in modulating lipid metabolism in HRMECs by regulating the expression of ACC1 and FASN, leading to cellular reprogramming. This reprogramming influences HRMEC proliferation, migration, and tube formation through the HIF-1α/TGF-β signaling pathway, ultimately contributing to pathological retinal neovascularization. These findings provide new insights into the role of SREBF1 in angiogenesis within the context of ROP, offering potential therapeutic targets for the management and treatment of this disease.
早产儿视网膜病变（ROP）是一种增殖性视网膜血管疾病，严重影响早产儿的视觉发育，可能导致不可逆转的视力丧失甚至失明。尽管其具有重要意义，但该疾病的潜在机制仍未得到充分了解。在本研究中，我们利用氧诱导性视网膜病变（OIR）小鼠模型并进行内皮功能测定，以探讨固醇调节元件结合蛋白1（SREBF1）在ROP发病机制中的作用。通过蛋白质免疫印迹法、逆转录-定量聚合酶链反应（RT-qPCR）和免疫荧光染色技术研究了SREBF1的表达水平及其下游靶点。此外，采用免疫共沉淀法（Co-IP）来研究其中涉及的分子机制。我们的结果表明，在OIR小鼠模型和缺氧的原代人视网膜微血管内皮细胞（HRMECs）中，SREBF1的表达均显著增加。体内和体外干预均显示出在减少病理性新生血管形成方面具有显著疗效。重要的是，我们发现SREBF1通过调节乙酰辅酶A羧化酶1（ACC1）和脂肪酸合酶（FASN）的表达在HRMECs中调节脂质代谢发挥关键作用，从而导致细胞重编程。这种重编程通过缺氧诱导因子-1α（HIF-1α）/转化生长因子-β（TGF-β）信号通路影响HRMEC的增殖、迁移和管腔形成，最终促成病理性视网膜新生血管形成。这些发现为SREBF1在ROP背景下的血管生成中的作用提供了新的见解，为该疾病的管理和治疗提供了潜在的治疗靶点。
