ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries.
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.
Wang
Li
L
Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing, PR China.
Zheng
Jingang
J
Bai
Xue
X
Liu
Bo
B
Liu
Chuan-Ju
CJ
Xu
Qingbo
Q
Zhu
Yi
Y
Wang
Nanping
N
Kong
Wei
W
Wang
Xian
X
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
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