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(Circulation Research. 2009;104:688.)
© 2009 American Heart Association, Inc.

Integrative Physiology

ADAMTS-7 Mediates Vascular Smooth Muscle Cell Migration and Neointima Formation in Balloon-Injured Rat Arteries

Li Wang, Jingang Zheng, Xue Bai, Bo Liu, Chuan-ju Liu, Qingbo Xu, Yi Zhu, Nanping Wang, Wei Kong, Xian Wang

From the Department of Physiology and Pathophysiology (L.W., X.B., B.L., Y.Z., N.W., W.K., X.W.), School of Basic Medical Sciences, Peking University, Beijing, People’s Republic of China; Key Laboratory of Molecular Cardiovascular Science (L.W., X.B., B.L., Y.Z., N.W., W.K., X.W.), Ministry of Education, Beijing, People’s Republic of China; Department of Cardiology (J.Z.), China-Japan Friendship Hospital, Beijing, People’s Republic of China; Department of Orthopaedic Surgery and Department of Cell Biology (C.-j.L.), New York University School of Medicine; and Cardiovascular Division (Q.X.), The James Black Centre, Kings College London, United Kingdom.

Correspondence to Wei Kong, Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100083, People’s Republic of China. E-mail kongw{at}bjmu.edu.cn

The migration of vascular smooth muscle cells (VSMCs) plays an essential role during the development of atherosclerosis and restenosis. Extensive studies have implicated the importance of extracellular matrix (ECM)-degrading proteinases in VSMC migration. A recently described family of proteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), is capable of degrading vascular ECM proteins. Here, we sought to determine whether ADAMTS-7 is involved in VSMC migration and neointima formation in response to vascular injury. ADAMTS-7 protein accumulated preferentially in neointima of the carotid artery wall after balloon injury. In primary VSMCs, ADAMTS-7 level was enhanced by the proinflammatory cytokine tumor necrosis factor and growth factor platelet-derived growth factor-BB. ADAMTS-7 overexpression greatly accelerated and small interfering RNA knockdown markedly retarded VSMC migration/invasion in vitro. In addition, luminal delivery of ADAMTS-7 adenovirus to carotid arteries exacerbated intimal thickening nearly sixfold 7 days after injury. Conversely, perivascular administration of ADAMTS-7 small interfering RNA but not scramble small interfering RNA to injured arteries attenuated intimal thickening by 50% at 14 days after injury. Furthermore, ADAMTS-7 mediated degradation of the vascular ECM cartilage oligomeric matrix protein (COMP) in injured vessels. Replenishing COMP circumvented the promigratory effect of ADAMTS-7 on VSMCs. Enforced expression of COMP significantly suppressed VSMC migration and neointima formation postinjury, which indicates that ADAMTS-7 facilitated intimal hyperplasia through degradation of inhibitory matrix protein COMP. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and postangioplasty restenosis.

Key Words: metalloproteinase • vascular smooth muscle cell migration • neointima formation • extracellular matrix