心肌素调控多能血管干细胞在血管损伤后狭窄中的作用及机制

The proliferation of smooth muscle cells(SMCs) is a major pathological mechanism of post-injury vascular stenosis. The latest theory studies showed that proliferative SMCs in blood vessels are actually derived from multipotent stem cells(MVSCs)after injury , which challenges the classical theory of dedifferentiation of mature SMCs. However, the action and related mechanisms of MVSCs affecting post-injury vascular stenosis remains poorly understood. In our previous studies we found that the expression of myocardin in vascular wall was decreased accompanied by the rapidly proliferated and activated MVSCs which repopulate the tunica media after vascular injury. Our further studies revealed that specific microRNAs induced by myocardin can mediate proliferation and differentiation of cells. Therefore, we speculate that vascular injury affects the function of MVSCs by regulating related microRNAs through myocardin, hereby inducing stenosis. In order to prove this point, it will be necessary to confirm the effects of myocardin in injury-induced differentiation of MVSCs in vivo and vitro through changing the expression of genes. Then, it will be focused on verification of the role of the related microRNAs and their target genes on promoting vascular stenosis by injury. Therefore, the project might have theoretical significance and important implications for leading to potential therapeutic targets for controlling injury-induced vascular stenosis.

平滑肌细胞增殖是血管损伤后狭窄的主要病理基础，最新的研究对经典的平滑肌细胞去分化理论提出挑战，发现增殖的平滑肌细胞实际上来源于多能血管干细胞（MVSCs），但其调控机制有待阐明。我们前期研究发现：在血管损伤后中膜出现大量MVSCs，且伴有心肌素（myocardin）表达下调；同时myocardin能够调控相关microRNAs介导细胞增殖分化等功能改变。因此推测，血管损伤通过myocardin调控microRNAs而影响MVSCs的功能，进而导致血管狭窄。本研究将通过不同方式操控基因表达,在细胞及动物模型上探讨myocardin基因在调节损伤诱导的MVSCs分化增殖中的作用，并对其相关的下游通路及靶基因进行甄别。本研究将丰富血管损伤后狭窄机制的认识，为其治疗提供新的理论依据和思路。

在血管损伤后中膜内MVSCs活化出现增殖迁移功能改变，且伴有心肌素（Myocardin， MYOCD）表达下调和自噬水平的升高。本研究通过不同方式操控基因表达,在细胞及动物模型上探讨MYOCD基因在调节损伤诱导的MVSCs增殖迁移中的作用，以及自噬在其中扮演的角色。结果发现：1. MYOCD表达下降促进MVSCs增殖和迁移加重血管损伤后内膜增生过程；2. 通过过表达MYOCD，证实MYOCD通过抑制MVSC内自噬水平调控其增殖分化能力参与血管损伤后内膜增生的过程；3. 通过基因敲除的方式抑制血管内自噬水平，发现自噬功能缺陷导致小鼠主动脉中膜增厚、顺应性降低、收缩力增强，最终表现为小鼠血压升高。研究结果进一步阐明血管损伤后MYOCD表达异常在血管内膜增生过程中的重要作用和具体机制。