title: ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries.
abstract: 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 alpha 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.
authors.affiliation: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Jingang
authors.initials: J
authors.lastname: Zheng
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Chuan-Ju
authors.initials: CJ
authors.lastname: Liu
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071118:ADAMTS7 Protein; D000818:Animals; D000077214:Becaplermin; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006965:Hyperplasia; D008297:Male; D064235:Matrilin Proteins; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017539:Tunica Intima / Q000201:enzymology* / Q000473:pathology
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000077214:Becaplermin; D051722:ADAM Proteins; D000071118:ADAMTS7 Protein; C539627:Adamts7 protein, rat