钙敏感受体诱导内质网-线粒体结构偶联异常参与高血压血管重塑的研究

Vascular remodeling, the core mechanism for the development of hypertension, which is characterized by vascular smooth muscle cells (VSMC) proliferation and migration induced by increased calcium. As a new calcium-regulated receptor, it is not clear that the role and the mechanism of the CaSR in hypertension-mediated vascular remodeling. In our preliminary study, we found that the expression of CaSR increased in the peripheral blood of the hypertensive patients. Meanwhile, the proliferation of VSMC and the upregulation of CaSR was observed, along with the abnormal morphology and membrane distance of endoplasmic reticulum (ER) and mitochondria (MT) in SHR rats. In addition, the blood pressure of the SHR rats could be reduced given by CaSR inhibitor. Therefore, it is tempting to speculate that it is the activation of CaSR-induced intracellular calcium increase leads to the abnormal of ER-MT physical coupling which results in the VSMC proliferation and vascular remodeling. In order to clarify the effect and mechanism of CaSR in hypertensive vascular remodeling, we will investigate the dynamic regulation of CaSR, its role in VSMC proliferation and the influence to ER-MT physical coupling. Our research will highlight that CaSR intervention might be a novel approach for vascular remodeling. The conclusion of this study may provide scientific evidence for the effective treatment of hypertension.

血管重塑是高血压进程中的核心机制，主要特征是钙离子浓度增加诱导了血管平滑肌细胞（VSMC）增殖和迁移。钙敏感受体（CaSR）作为新的调节钙离子受体，其在高血压血管重塑中的作用及机制未明。我们前期发现高血压病人外周血中CaSR表达增加；自发性高血压大鼠VSMC增殖，CaSR表达上调，内质网和线粒体结构改变，膜间距增大；给予CaSR抑制剂后大鼠血压下降。为此提出假说：“高血压时CaSR激活引起细胞内钙增加，导致内质网-线粒体结构偶联异常，诱导VSMC增殖和血管重塑；而干扰CaSR有望成为高血压防治的新靶点”。本课题拟从高血压病人、动物模型和细胞水平三个视角，研究高血压时CaSR表达的特点及规律，阐明CaSR在VSMC增殖中的作用，探讨CaSR表达对内质网-线粒体结构偶联的影响，揭示CaSR在高血压血管重塑中的分子机制，明确干扰CaSR可能是抑制血管重塑的新途径，为高血压的防治提供科学依据。

血管重塑是高血压进程中的核心机制，主要特征是钙离子浓度增加诱导了血管平滑肌细胞（VSMC）增殖和迁移。钙敏感受体（CaSR）作为新的调节钙离子受体，其在高血压血管重塑中的作用及机制未明。本课题组以WKY大鼠和自发性高血压大鼠VSMC和内皮细胞为研究对象，以血压检测、形态学、病理学、分子生物学等为手段，干预CaSR后观察VSMC和内皮细胞CaSR表达、胞内钙流、内质网和线粒体形态结构、内质网应激、线粒体分裂融合动态演变、自噬、细胞表型转换以及相关信号转导途径，分析CaSR的表达与高血压血管重塑的内在关系，提示CaSR激活引起细胞内钙增加，导致内质网-线粒体功能异常，诱导VSMC增殖和血管重塑；而干预CaSR可影响上述环节，因此高血压时CaSR激活介导细胞内钙流增加引起内质网应激和线粒体功能改变从而介导高血压血管重塑，抑制CaSR可能是抑制血管重塑的新途径，为高血压的防治提供科学依据。