PSPC1调控血管平滑肌细胞表型转化在血管内膜新生中的作用及机制研究

对于危及生命的冠状动脉粥样硬化患者，支架植入术是不可缺少的手段。然而，机械损伤后血管内膜新生导致的血管再狭窄是限制患者预后的突出的问题。其中血管平滑肌细胞的表型转化是血管内膜增生性疾病的重要环节。本课题前期研究发现，人冠状动脉粥样硬化斑块组织和小鼠颈动脉新生内膜组织中PSPC1的表达水平较正常组织减少，小鼠血管平滑肌细胞中敲减或过表达PSPC1影响平滑肌细胞的表型转化，推测PSPC1蛋白调控平滑肌细胞的表型转化参与血管内膜新生。本课题首先通过CRISPR/Cas9技术获得PSPC1基因敲除小鼠，观察PSPC1蛋白缺失对小鼠血管完整性的影响；其次利用PSPC1基因敲除雄鼠、同窝对照野生雄鼠和PSPC1慢病毒过表达雄鼠，研究PSPC1蛋白对血管内膜新生的影响；最后通过提取小鼠原代血管平滑肌细胞，探索PSPC1对血管平滑肌细胞表型转化的影响及潜在机制。为血管内膜新生的基因治疗提供潜在的有效靶点。

At present, the stent implantation is still indispensable for patients with life-threatening coronary artery atherosclerosis. However, the restenosis caused by neointima formation after the surgical injury is the most prominent problem which limits the outcome of patients. The phenotypic switching of vascular smooth muscle cells stimulated by growth factors is a key pathological factor in neointima formation. Our previous investigation of this study found that the expression level of PSPC1 in human coronary atherosclerotic plaques was lower than that in the normal coronary arteries. Similarly, the expression level of PSPC1 in the neointima of carotid arteries in mice was lower than that in normal carotid arteries. Knockdown or overexpression of PSPC1 regulated the phenotypes of the primary vascular smooth muscle cells of mice. These results suggested that PSPC1 may be involved in neointima formation. Firstly, we acquired the PSPC1 knockout mice by the CRISPR/Cas9 technology to investigate the effect of PSPC1 on maintaining the integrity and structure of vessels. Secondly, the PSPC1 knockout male mice, their wild-type male littermates and the PSPC1 overexpressed male mice were used to study the effect of PSPC1 in neointima formation. Last but not least, the primary vascular smooth muscle cells were abstracted from the PSPC1 knockout male mice and their wild-type male littermates and were used to explore the effects of PSPC1 on the phenotypic switching and the underlying mechanisms. These results may provide a potential target for the treatment of neointima formation effectively.