Zhu Zhenyu, Liu Hao, Feng Liyun, Lu Lihe, Zhu Jiahui, Liang Qingchun, Lan Zirong, Ye Yuanzhi, Wang Siyi, Chen An, Yan Jianyun
Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, 510280, PR China; Department of Cardiology, Tongde Hospital of Zhejiang Province, PR China.
Division of Vascular and Interventional Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical University, PR China.
Atherosclerosis. 2025 May;404:119190. doi: 10.1016/j.atherosclerosis.2025.119190. Epub 2025 Apr 8.
Extracellular matrix (ECM) proteases have been closely linked to the pathogenesis of vascular calcification. A disintegrin and metalloprotease with thrombospondin motifs-5 (ADAMTS5) is an ECM-degrading enzyme involved in ECM remodeling. Versican, a critical ECM component in the arteries, can be proteolytically cleaved by ADAMTS5 and activates integrin β1. However, whether ADAMTS5 is involved in the regulation of the pathogenesis of vascular calcification remains unclear. This study investigates the regulatory role of ADAMTS5 in vascular calcification and its mechanistic link to versican-integrin β1/FAK signaling.
Western blot, immunofluorescence, and immunohistochemistry analysis revealed that ADAMTS5 expression was significantly downregulated in rat and human vascular smooth muscle cells (VSMCs), as well as in rat and human arteries during vascular calcification. In addition, both pharmacological inhibition of ADAMTS5 and knockdown of ADAMTS5 by siRNA significantly aggravated mineral deposition in rat and human VSMCs under osteogenic conditions. Moreover, adenovirus-mediated ADAMTS5 overexpression markedly attenuated calcification of VSMCs and aortic calcification in rats with chronic kidney disease. Furthermore, inhibition of ADAMTS5 promoted aortic calcification in VitD-overloaded mice. Mechanistically, overexpression of ADAMTS5 significantly reduced versican protein levels, and inhibited integrin β1 and FAK phosphorylation in rat VSMCs, but increased versikine protein levels. Moreover, either knockdown of versican or pharmacological inhibition of FAK phosphorylation repressed VSMC calcification mediated by loss of ADAMTS5.
We have demonstrated for the first time that ADAMTS5 deficiency promotes versican accumulation and activates integrin β1/FAK signaling. These findings suggest ADAMTS5 as a potential therapeutic target for vascular calcification.
细胞外基质（ECM）蛋白酶与血管钙化的发病机制密切相关。含血小板反应蛋白基序的解聚素和金属蛋白酶-5（ADAMTS5）是一种参与ECM重塑的ECM降解酶。多功能蛋白聚糖是动脉中一种关键的ECM成分，可被ADAMTS5蛋白水解切割并激活整合素β1。然而，ADAMTS5是否参与血管钙化发病机制的调控仍不清楚。本研究探讨ADAMTS5在血管钙化中的调控作用及其与多功能蛋白聚糖-整合素β1/黏着斑激酶（FAK）信号通路的机制联系。
蛋白质免疫印迹、免疫荧光和免疫组织化学分析显示，在大鼠和人类血管平滑肌细胞（VSMC）以及血管钙化过程中的大鼠和人类动脉中，ADAMTS5表达显著下调。此外，在成骨条件下，ADAMTS5的药理学抑制和通过小干扰RNA（siRNA）敲低ADAMTS5均显著加重了大鼠和人类VSMC中的矿物质沉积。此外，腺病毒介导的ADAMTS5过表达显著减轻了慢性肾病大鼠VSMC的钙化和主动脉钙化。此外，抑制ADAMTS5促进了维生素D过载小鼠的主动脉钙化。机制上，ADAMTS5过表达显著降低了多功能蛋白聚糖蛋白水平，并抑制了大鼠VSMC中整合素β1和FAK的磷酸化，但增加了多功能蛋白聚糖趋化因子蛋白水平。此外，敲低多功能蛋白聚糖或FAK磷酸化的药理学抑制均抑制了由ADAMTS5缺失介导的VSMC钙化。
我们首次证明ADAMTS5缺乏促进多功能蛋白聚糖积累并激活整合素β1/FAK信号通路。这些发现表明ADAMTS5是血管钙化的潜在治疗靶点。
