Wang Li, Wang Xian, Kong Wei
Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Beijing, China.
Sheng Li Xue Bao. 2010 Aug 25;62(4):285-94.
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 bona fide 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 alpha7beta1. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and postangioplasty restenosis.
血管重塑被认为是动脉粥样硬化和再狭窄过程中的一个基本过程。累积研究表明，细胞外基质（ECM）降解酶在血管重塑过程中起关键作用。含血小板反应蛋白基序的解聚素和金属蛋白酶（ADAMTS）家族是最近发现的一个金属蛋白酶家族，它也具有降解ECM的能力。ADAMTS家族由19个成员组成，与包括发育、血管生成、凝血等多种生理过程有关。ADAMTS成员的异常表达或功能与许多疾病状态有关，如关节炎、癌症、血小板减少性紫癜，但在心血管疾病方面鲜有描述。本综述总结了ADAMTS-7在血管重塑中作用的最新进展。我们回顾了ADAMTS-7的结构、组织分布、底物、表达和调控，特别强调了ADAMTS-7对其底物软骨寡聚基质蛋白（COMP）在维持血管稳态中的精细调节。通过使用大鼠颈动脉球囊损伤模型模拟体内血管损伤，我们发现ADAMTS-7蛋白优先在新生内膜中积累，主要定位于血管平滑肌细胞（VSMC）。腺病毒介导的ADAMTS-7过表达在体内和体外均大大加速了VSMC的迁移和增殖，并随后加重了损伤后新生内膜的增厚。相反，siRNA介导的ADAMTS-7敲低确实抑制了培养的VSMC和损伤动脉中VSMC的迁移和增殖，并最终改善了新生内膜面积。进一步的研究表明ADAMTS-7通过降解其底物COMP促进VSMC迁移。此外，我们阐明COMP具有通过与整合素α7β1相互作用来维持VSMC收缩表型的能力。因此，ADAMTS-7可能成为动脉粥样硬化和血管成形术后再狭窄的一个新的治疗靶点。
