Abu El-Asrar Ahmed M, Nawaz Mohd I, Ahmad Ajmal, Siddiquei Mairaj, Allegaert Eef, Adyns Lowie, Vanbrabant Lotte, Gikandi Priscilla W, De Hertogh Gert, Struyf Sofie, Opdenakker Ghislain
Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia.
Dr. Nasser Al-Rashid Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia.
Cells. 2025 Jan 9;14(2):85. doi: 10.3390/cells14020085.
The protease, a disintegrin and metalloproteinase with thrombospondin type 1 motif member 13 (ADAMTS13), known to cleave only the von Willebrand factor (VWF), has powerful regulatory effects on microvascular platelet adhesion, thrombosis, inflammation, and endothelial dysfunction. We study the protection against diabetes-induced retinal injury in experimental rats by supplementation with recombinant ADAMTS13. We compare human epiretinal membranes and vitreous samples from nondiabetic subjects and patients with proliferative diabetic retinopathy (PDR) and extend in vitro analyses with the use of various immunodetection and spectrofluorimetric methods on rat retina and human retinal glial and endothelial cell cultures. Functional studies include the assessment of the blood-retinal barrier (BRB), cell adhesion, and in vitro angiogenesis. In epiretinal membranes, endothelial cells and monocytes/macrophages express ADAMTS13. The levels of VWF, the platelet marker CD41, ADAMTS13, and the biomarkers of endothelial cell injury soluble VE-cadherin and soluble syndecan-1 are increased in PDR vitreous. ADAMTS13 is downregulated in diabetic rat retinas. The intravitreal administration of ADAMTS13 attenuates diabetes-induced BRB breakdown, the downregulation of VE-cadherin and β-catenin, and the upregulation of VWF, CD41, phospho-ERK1/2, HMGB1, VCAM-1, and ICAM-1. In Müller cells, ADAMTS13 attenuates MCP-1, MMP-9, and ROS upregulation induced by diabetic mimetic conditions. In HRMECs, ADAMTS13 attenuates the shedding of the soluble VE-cadherin and soluble syndecan-1 and the levels of phospho-ERK1/2, MCP-1, fractalkine, and ROS induced by diabetic mimetic conditions, the upregulation of ICAM-1 and VCAM-1 elicited by TNF-α, the adherence of monocytes induced by TNF-α, and VEGF-induced migration of human retinal microvascular endothelial cells. Our findings suggest that enhancing ADAMTS13 levels in situ ameliorates diabetes-induced retinal inflammation and vascular dysfunction.
蛋白酶解整合素与金属蛋白酶13（ADAMTS13），已知其仅能裂解血管性血友病因子（VWF），对微血管血小板黏附、血栓形成、炎症及内皮功能障碍具有强大的调节作用。我们通过补充重组ADAMTS13来研究其对实验性大鼠糖尿病性视网膜损伤的保护作用。我们比较了非糖尿病受试者和增殖性糖尿病视网膜病变（PDR）患者的人视网膜前膜和玻璃体样本，并使用各种免疫检测和荧光光谱法对大鼠视网膜以及人视网膜神经胶质细胞和内皮细胞培养物进行体外分析。功能研究包括血视网膜屏障（BRB）评估、细胞黏附及体外血管生成。在视网膜前膜中，内皮细胞和单核细胞/巨噬细胞表达ADAMTS13。PDR玻璃体中VWF、血小板标志物CD41、ADAMTS13以及内皮细胞损伤生物标志物可溶性血管内皮钙黏蛋白（sVE-cadherin）和可溶性多配体蛋白聚糖-1的水平升高。ADAMTS13在糖尿病大鼠视网膜中表达下调。玻璃体内注射ADAMTS13可减轻糖尿病诱导的BRB破坏、VE-cadherin和β-连环蛋白的下调以及VWF、CD41、磷酸化细胞外信号调节激酶1/2（p-ERK1/2）、高迁移率族蛋白B1（HMGB1）、血管细胞黏附分子-1（VCAM-1）和细胞间黏附分子-1（ICAM-1）的上调。在 Müller 细胞中，ADAMTS13 可减轻模拟糖尿病条件诱导的单核细胞趋化蛋白-1（MCP-1）、基质金属蛋白酶-9（MMP-9）和活性氧（ROS）的上调。在人视网膜微血管内皮细胞（HRMECs）中，ADAMTS13 可减轻模拟糖尿病条件诱导的可溶性 VE-cadherin 和可溶性多配体蛋白聚糖-1 的脱落以及 p-ERK1/2、MCP-1、 fractalkine 和 ROS 的水平，减轻肿瘤坏死因子-α（TNF-α）诱导的 ICAM-1 和 VCAM-1 的上调、TNF-α 诱导的单核细胞黏附以及血管内皮生长因子（VEGF）诱导的人视网膜微血管内皮细胞迁移。我们的研究结果表明，原位提高ADAMTS13水平可改善糖尿病诱导的视网膜炎症和血管功能障碍。
