在糖尿病视网膜病变中，PLK-1/Ang-2介导的adamts13介导的血管生成与VEGF无关。

IF 2.7 2区医学 Q1 OPHTHALMOLOGY

Experimental eye research Pub Date : 2025-09-08 DOI:10.1016/j.exer.2025.110633

Bo Li , Yujin Jiang , Yiken Huang , Xinyu Zhang , Zhi Zheng , Lisha Ni , Shuzhi Zhao

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引用次数: 0

摘要

目的：一种具有血小板反应蛋白1型基序13 （ADAMTS13）的崩解素样和金属蛋白酶被发现增加并与糖尿病视网膜病变（DR）相关。方法：采用western blot、实时定量PCR、免疫荧光和ELISA检测人视网膜微血管内皮细胞（HRMVECs）、增殖性DR患者玻璃体样本和糖尿病小鼠模型中ADAMTS13的表达情况。通过细胞活力、试管形成、Transwell迁移和伤口愈合试验研究了ADAMTS13基因敲低对HRMVECs细胞的影响，并通过视网膜胰蛋白酶消化和Evans蓝染料泄漏试验研究了糖尿病小鼠的影响。采用RNA-seq技术研究ADAMTS13敲低介导的新生血管减少的分子机制。结果：本研究显示，在患者中，高糖上调玻璃体ADAMTS13水平；在体外，高葡萄糖浓度上调ADAMTS13，并伴有细胞增殖、迁移和管形成的增加。ADAMTS13敲除降低了这些变化。在体内，糖尿病小鼠视网膜血管渗漏和脱细胞毛细血管增加，抑制ADAMTS13可减少这些变化。此外，本研究表明ADAMTS13调节DR中不依赖于血管内皮生长因子（VEGF）的马球样激酶-1 (PLK-1)/血管生成素-2 （Ang-2）轴。结论：我们的研究揭示了ADAMTS13通过PLK-1/Ang-2信号通路参与DR的发展，以及血管生成。靶向adamts13相关通路可能成为DR患者的一种新的治疗方法。

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ADAMTS13-mediated angiogenesis by PLK-1/Ang-2 is independent of VEGF in diabetic retinopathy

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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来源期刊

Experimental eye research 医学-眼科学

CiteScore

6.80

自引率

5.90%

发文量

323

审稿时长

66 days

期刊介绍： The primary goal of Experimental Eye Research is to publish original research papers on all aspects of experimental biology of the eye and ocular tissues that seek to define the mechanisms of normal function and/or disease. Studies of ocular tissues that encompass the disciplines of cell biology, developmental biology, genetics, molecular biology, physiology, biochemistry, biophysics, immunology or microbiology are most welcomed. Manuscripts that are purely clinical or in a surgical area of ophthalmology are not appropriate for submission to Experimental Eye Research and if received will be returned without review.