Hao Feng, Zhang Fuqiang, Wu Daniel Dongwei, An Dong, Shi Jing, Li Guohong, Xu Xuemin, Cui Mei-Zhen
Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
Science Research Center, China-Japan Union Hospital of Jilin University, Changchun, China.
Am J Physiol Cell Physiol. 2016 Dec 1;311(6):C975-C984. doi: 10.1152/ajpcell.00227.2016. Epub 2016 Oct 19.
Vascular smooth muscle cell (SMC) migration is an essential step involved in neointimal formation in restenosis and atherosclerosis. Lysophosphatidic acid (LPA) is a bioactive component of oxidized low-density lipoprotein and is produced by activated platelets, implying that LPA influences vascular remodeling. Our previous study revealed that matricellular protein CCN1, a prominent extracellular matrix (ECM) protein, mediates LPA-induced SMC migration in vitro. Here we examined the role of CCN1 in LPA-induced neointimal formation. By using LPA infusion of carotid artery in a mouse model, we demonstrated that LPA highly induced CCN1 expression (approximately six- to sevenfold) in neointimal lesions. Downregulation of CCN1 expression with the specific CCN1 siRNA in carotid arteries blocked LPA-induced neointimal formation, indicating that CCN1 is essential in LPA-induced neointimal formation. We then used LPA receptor knockout (LPA-/-, LPA-/-, and LPA-/-) mice to examine LPA receptor function in CCN1 expression in vivo and in LPA-induced neointimal formation. Our data reveal that LPA deficiency, but not LPA or LPA deficiency, prevents LPA-induced CCN1 expression in vivo in mouse carotid arteries. We also observed that LPA deficiency blunted LPA infusion-induced neointimal formation, indicating that LPA is the major mediator for LPA-induced vascular remodeling. Our in vivo model of LPA-induced neointimal formation established a key role of the ECM protein CCN1 in mediating LPA-induced neointimal formation. Our data support the notion that the LPA-CCN1 axis may be the central control for SMC migration and vascular remodeling. CCN1 may serve as an important vascular disease marker and potential target for vascular therapeutic intervention.
血管平滑肌细胞（SMC）迁移是再狭窄和动脉粥样硬化中新生内膜形成所涉及的一个关键步骤。溶血磷脂酸（LPA）是氧化型低密度脂蛋白的一种生物活性成分，由活化的血小板产生，这表明LPA会影响血管重塑。我们之前的研究表明，基质细胞蛋白CCN1是一种重要的细胞外基质（ECM）蛋白，在体外介导LPA诱导的SMC迁移。在此，我们研究了CCN1在LPA诱导的新生内膜形成中的作用。通过在小鼠模型中对颈动脉进行LPA灌注，我们证明LPA在新生内膜病变中高度诱导CCN1表达（约6至7倍）。在颈动脉中用特异性CCN1 siRNA下调CCN1表达可阻断LPA诱导的新生内膜形成，表明CCN1在LPA诱导的新生内膜形成中至关重要。然后，我们使用LPA受体敲除（LPA - / - 、LPA - / - 和LPA - / - ）小鼠来研究LPA受体在体内CCN1表达以及LPA诱导的新生内膜形成中的功能。我们的数据显示，LPA缺乏而非LPA或LPA缺乏可阻止小鼠颈动脉体内LPA诱导的CCN1表达。我们还观察到LPA缺乏减弱了LPA灌注诱导的新生内膜形成，表明LPA是LPA诱导血管重塑的主要介质。我们建立的LPA诱导新生内膜形成的体内模型确立了ECM蛋白CCN1在介导LPA诱导的新生内膜形成中的关键作用。我们的数据支持这样一种观点，即LPA - CCN1轴可能是SMC迁移和血管重塑的核心控制机制。CCN1可能作为一种重要的血管疾病标志物以及血管治疗干预的潜在靶点。
