Li Bo, Jiang Yujin, Huang Yikeng, Zhang Xinyu, Zheng Zhi, Ni Lisha, Zhao Shuzhi
Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai, 200080, China; Department of Ophthalmology, The Fourth Affiliated Hospital of Soochow University, 9 Chongwen Road, Suzhou Industrial Park, Suzhou, Jiangsu Province, 215123, China.
Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai, 200080, China.
Exp Eye Res. 2025 Nov;260:110633. doi: 10.1016/j.exer.2025.110633. Epub 2025 Sep 8.
A disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) has been found to increase and to be associated with diabetic retinopathy (DR). The study aimed to identify the role of ADAMTS13 in the pathogenesis of angiogenesis in DR.
ADAMTS13 expression was evaluated in human retinal microvascular endothelial cells (HRMVECs), vitreous sample from patients with proliferative DR and diabetic mice model using Western blot, real time-quantitative PCR, immunofluorescence and ELISA. The effects of ADAMTS13 knockdown were studied in HRMVECs employing cell viability, tube formation, Transwell migration and wound healing assays and in diabetic mice using retinal trypsin digestion and Evans blue dye leakage assays. RNA-seq was applied to study the molecular mechanism of ADAMTS13 knockdown-mediated decreased neovascularization.
This study revealed that, among patients, high-glucose upregulated vitreous ADAMTS13 levels; in vitro, high-glucose concentration upregulated ADAMTS13, accompanied by increased cell proliferation, migration, and tube formation. ADAMTS13 knockdown decreased these changes. In vivo, in diabetic mice, retinal vascular leakage and acellular capillaries increased, and inhibition of ADAMTS13 reduced these changes. Furthermore, this study demonstrated that ADAMTS13 regulated the polo-like kinase-1 (PLK-1)/angiopoietin-2 (Ang-2) axis independent of vascular endothelial growth factor (VEGF) in DR.
Our study revealed the involvement of ADAMTS13 in DR development, as well as in angiogenesis through the PLK-1/Ang-2 signaling pathway. Targeting ADAMTS13-related pathways involved could serve as a novel therapeutic approach for patients with DR.
已发现具有血小板反应蛋白1型基序的解整合素样金属蛋白酶13（ADAMTS13）增加且与糖尿病视网膜病变（DR）相关。本研究旨在确定ADAMTS13在DR血管生成发病机制中的作用。
使用蛋白质免疫印迹法、实时定量聚合酶链反应、免疫荧光法和酶联免疫吸附测定法，在人视网膜微血管内皮细胞（HRMVECs）、增殖性DR患者的玻璃体样本和糖尿病小鼠模型中评估ADAMTS13的表达。采用细胞活力、管腔形成、Transwell迁移和伤口愈合试验研究ADAMTS13敲低在HRMVECs中的作用，并使用视网膜胰蛋白酶消化和伊文思蓝染料渗漏试验在糖尿病小鼠中进行研究。应用RNA测序研究ADAMTS13敲低介导的新生血管形成减少的分子机制。
本研究表明，在患者中，高糖上调了玻璃体中ADAMTS13的水平；在体外，高糖浓度上调了ADAMTS13，同时细胞增殖、迁移和管腔形成增加。ADAMTS13敲低减少了这些变化。在体内，糖尿病小鼠的视网膜血管渗漏和无细胞毛细血管增加，而抑制ADAMTS13可减少这些变化。此外，本研究证明ADAMTS13在DR中独立于血管内皮生长因子（VEGF）调节 polo样激酶1（PLK-1）/血管生成素-2（Ang-2）轴。
我们的研究揭示了ADAMTS13参与DR的发展以及通过PLK-1/Ang-2信号通路参与血管生成。靶向涉及的ADAMTS13相关途径可能成为DR患者的一种新的治疗方法。
