ADAMTS-7, a novel proteolytic culprit in vascular remodeling

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WANG Li(Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education,Beijing 100191, China)
WANG Xian(Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education,Beijing 100191, China)
KONG Wei(Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education,Beijing 100191, China)
Journal Title:
Volume 62, Issue 04, 2010
Key Word:
ADAMTS-7;COMP;vascular smooth muscle;migration;proliferation

Abstract: Vascular remodeling is being recognized as a fundamental process during atherosclerosis and restenosis. Cumulative studies have demonstrated that extracellular matrix (ECM) degrading enzymes play a critical role during vascular remodeling. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family is a recently identified metalloproteinase family which also has capacity to degrade ECM. ADAMTS family consists of 19 members and has been linked to a variety of physiological processes including development, angiogenesis, coagulation etc. Aberrant expression or function of ADAMTS members have been implicated to many disease states such as arthritis, cancer, thrombocytopenic purpura, but barely described with regard to cardiovascular disease. This review summarizes the recent advance with respect to the role of ADAMTS-7 in vascular remodeling. We review the structure, tissue distribution, substrate, expression and regulation of ADAMTS-7, especially highlight the fine tune by ADAMTS-7 of its substrate cartilage oligomeric matrix protein (COMP) in maintaining vascular homeostasis. By use of rat carotid artery balloon injury model to mimic vascular injury in vivo, we found that ADAMTS-7 protein was accumulated preferentially in neointima and mainly localized in vascular smooth muscle cells (VSMCs). Adenovirus-elicited ADAMTS-7 overexpression greatly accelerated VSMCs migration and proliferation both in vivo and in vitro, and subsequently aggravated neointima thickening post-injury. Conversely, siRNA-mediated ADAMTS-7 knock down bonafide inhibited VSMCs migration and proliferation in cultured VSMCs and injured arteries, and ultimately ameliorated neointima area. Further studies demonstrated that ADAMTS-7 facilitated VSMCs migration through degradation of its substrate COMP. Moreover, we elucidated that COMP has the capacity to maintain the contractile phenotype of VSMCs through interacting with integrin α7β1. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and postangioplasty restenosis.

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