2. Academic Validation
  3. Loss of ADAMTS5 promotes vascular calcification via versican/integrin β1/FAK signal

Loss of ADAMTS5 promotes vascular calcification via versican/integrin β1/FAK signal

  • Atherosclerosis. 2025 May:404:119190. doi: 10.1016/j.atherosclerosis.2025.119190.
Zhenyu Zhu 1,  Hao Liu 2,  Liyun Feng 3,  Lihe Lu 4,  Jiahui Zhu 3,  Qingchun Liang 5,  Zirong Lan 3,  Yuanzhi Ye 3,  Siyi Wang 3,  An Chen 6,  Jianyun Yan 7
Affiliations

Affiliations

  • 1 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.
  • 2 Division of Vascular and Interventional Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical University, PR China.
  • 3 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.
  • 4 Department of Pathophysiolgy, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, 510080, PR China.
  • 5 Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510665, PR China.
  • 6 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. Electronic address: chenan805@163.com.
  • 7 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. Electronic address: yanjy790@smu.edu.cn.
PMID: 40215897 DOI: 10.1016/j.atherosclerosis.2025.119190
Abstract

Introduction: 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.

Methods and results: 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 VitD3-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.

Conclusions: 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.

Keywords

ADAMTS5; Chronic kidney disease; Integrin β1; Vascular calcification; Vascular smooth muscle cell; Versican.

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