ADAMTS-7 Mediates Vascular Smooth Muscle Cell Migration and Neointima Formation in Balloon-Injured Rat Arteries
ADAMTS-7 Mediates Vascular Smooth Muscle Cell Migration and Neointima Formation in Balloon-Injured Rat Arteries
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ADAMTS-7 介导球囊损伤大鼠动脉中的血管平滑肌细胞迁移和新内膜形成
DOI：
10.1161/circresaha.108.188425
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发表时间：
2009-03-13
影响因子：
20.1
通讯作者：
Wang, Xian
中科院分区：
文献类型：
--
作者：
Wang, Li;Zheng, Jingang;Wang, Xian
血管平滑肌细胞(VSMCs)的迁移在动脉粥样硬化和再狭窄的发生发展过程中起着至关重要的作用。大量研究表明细胞外基质(ECM)降解蛋白在VSMC迁移中的重要性。最近发现的一个蛋白水解酶家族，是一种具有血栓反应蛋白模体的去整合素和金属蛋白酶(ADAMTS)，能够降解血管ECM蛋白。在这里，我们试图确定ADAMTS-7是否参与血管损伤后VSMC的迁移和新生内膜的形成。球囊损伤后，ADAMTS-7蛋白在颈动脉壁新生内膜中优先积聚。在原代VSMCs中，促炎症细胞因子肿瘤坏死因子α和生长因子血小板衍生生长因子BB上调了ADAMTS-7的水平。ADAMTS-7的过表达大大加速了VSMC的体外迁移/侵袭，而小干扰RNA的敲除明显抑制了VSMC的迁移/侵袭。此外，将ADAMTS-7腺病毒腔内注射到颈动脉后，损伤后7天的颈动脉内膜厚度增加了近6倍。相反，血管周围应用ADAMTS-7小干扰RNA，但不干扰小干扰RNA到损伤动脉，在损伤后14天，血管内膜增厚减轻50%。此外，ADAMTS-7还介导了损伤血管中ECM软骨寡聚基质蛋白(COMP)的降解。补充COMP可规避ADAMTS-7对VSMC的迁移作用。COMP的增强表达显著抑制了损伤后VSMC的迁移和新生内膜的形成，表明ADAMTS-7通过降解抑制基质蛋白COMP促进了内膜的增殖。因此，ADAMTS-7可能成为治疗动脉粥样硬化和血管成形术后再狭窄的新靶点。(中国保监会决议2009；104：688-698。)
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. (Circ Res. 2009; 104: 688-698.)