整合素α5通过激活TAK-1/NF-κB驱动糖尿病视网膜病变中的血管生成。

ITGA5 drives angiogenesis in diabetic retinopathy via TAK-1/NF-kB activation.

作者信息

Kan Feifei, Wang Di, Li Sijia, Gao Yi, Wang Jianwen

机构信息

Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.

出版信息

Hum Cell. 2025 May 23;38(4):105. doi: 10.1007/s13577-025-01233-8.

DOI:10.1007/s13577-025-01233-8

PMID:40410450

Abstract

Diabetic retinopathy is a retinal damage, which causes vision impairment and blindness. Integrin Subunit Alpha 5 (ITGA5) regulates angiogenic response, but its roles in diabetic retinopathy remain unclear. In this work, diabetes mellitus was induced in rats by streptozotocin. ITGA5 interference was achieved by intravitreal delivery of adeno-associated virus. Upregulation of ITGA5 was found in diabetic rat retinal tissues. ITGA5 knockdown decreased the neovascularization, acellular capillary formation, and pericytes. The protein expression of vascular endothelial growth factor (VEGFA), vascular adhesion molecule-1(VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) was reduced after ITGA5 interference. Besides, ITGA5 knockdown decreased the phosphorylation level of FAK, TAK-1, and p65. In vitro, rat retinal microvascular endothelial cells (RRMECs) were cultured under high glucose condition to stimulate diabetic environment. ITGA5 knockdown inhibited VEGFA secretion, tube formation, cell invasion, and migration. Upregulation of VCAM-1 and ICAM-1 that induced by high glucose was reversed by ITGA5 silencing. ITGA5 knockdown blocked the activation of TAK-1/NF-kB pathway in RRMECs. Additionally, in oxygen-induced retinopathy model, ITGA5 interference inhibited pathological neovascularization. These results demonstrate that ITGA5 contributes to the angiogenesis in diabetic retinopathy by activating TAK-1/NF-kB pathway.

摘要

糖尿病视网膜病变是一种视网膜损伤，可导致视力损害和失明。整合素亚基α5（ITGA5）调节血管生成反应，但其在糖尿病视网膜病变中的作用尚不清楚。在这项研究中，通过链脲佐菌素诱导大鼠患糖尿病。通过玻璃体内注射腺相关病毒实现ITGA5干扰。在糖尿病大鼠视网膜组织中发现ITGA5上调。ITGA5基因敲低减少了新生血管形成、无细胞毛细血管形成和周细胞。ITGA5干扰后，血管内皮生长因子（VEGFA）、血管细胞黏附分子-1（VCAM-1）和细胞间黏附分子-1（ICAM-1）的蛋白表达降低。此外，ITGA5基因敲低降低了FAK、TAK-1和p65的磷酸化水平。在体外，将大鼠视网膜微血管内皮细胞（RRMECs）在高糖条件下培养以模拟糖尿病环境。ITGA5基因敲低抑制了VEGFA分泌、管腔形成、细胞侵袭和迁移。ITGA5沉默逆转了高糖诱导的VCAM-1和ICAM-1上调。ITGA5基因敲低阻断了RRMECs中TAK-1/NF-κB信号通路的激活。此外，在氧诱导的视网膜病变模型中，ITGA5干扰抑制了病理性新生血管形成。这些结果表明，ITGA5通过激活TAK-1/NF-κB信号通路促进糖尿病视网膜病变中的血管生成。