MKL1介导的分化型血管平滑肌细胞增殖在动静脉内瘘外向重塑中的作用及机制

动静脉内瘘（AVF）在成熟过程中瘘静脉会发生适应性重塑即外向重塑，而重塑失败可造成AVF成熟失败，但机制尚未阐明。血管平滑肌细胞的（VSMC）增殖与分化可参与血管重塑性疾病，MKL1作为Myocardin相关转录因子家族中的一员可诱导VSMC增殖与分化。我们的预实验发现:在AVF瘘静脉成熟过程中，VSMC在保持分化表型的同时高度增生；MKL1在人和小鼠AVF成熟瘘静脉标本中表达升高，VSMC特异性敲除MKL1可阻碍AVF外向重塑，但MKL1如何介导这个过程尚不清楚。本课题拟在预实验基础上，采用体外细胞模型、VSMC特异性YAP/MKL1基因敲除AVF小鼠模型和临床AVF患者瘘静脉标本作为研究对象，探讨MKL1介导分化型VSMC增殖在AVF外向重塑中的病理生理意义及YAP如何调控MKL1表达并在其中发挥作用，期望为外向重塑失败所致AVF成熟失败提供新的治疗靶点。

The venous outflow of arteriovenous fistula may have adaptive outward remodeling-outward remodeling (vascular wall thickening and lumen diameter enlargement). Impaired outward remodeling results in maturation failure of AVF, but the pathophysiology of arteriovenous fistula (AVF) maturation failure is not completely understood now. Our previous studies found that in the process of the maturation of fistula vein, VSMC maintained the differentiated phenotype of VSMC with high proliferation in AVF mice. The MKL1 expression was increased in mature AVF specimens , and VSMC conditional knockout of MKL1 can inhibit outward remodeling of AVF maturation. Based on the above results of previous studies, we are going to investigate that the pathophysiological significance of MKL1 mediated differentiated VSMC proliferation in the outward remodeling of AVF and how YAP regulates the expression of MKL1 in above processes in cultured human VSMCs, VSMC conditional YAP/MKL1 knockout mice and patients with AVF. By this investigation, we expect to clarify a new therapeutic target for the maturation failure caused by the impaired outward remodeling of AVF.