EphB4通过影响血管平滑肌细胞分化表型的改变抑制静脉移植物内膜增生

Autogenous vein graft is a frequently used surgical therapy to treat the occlusive disease of lower extremity. The most distinctive property of the vein graft is the adaptive remodeling to arterial environment, which is called vein graft adaptation. Excessive adaptation is characterized by increased wall thickness and decreased lumen diameter, which leads to ultimately vein graft failure. Both vascular smooth muscle cell (VSMC) proliferation/migration and neointimal hyperplasia are important components of vein graft adaptation. Our previous data showed that EphB4 as a receptor tyrosine kinase is activated in vein graft and inhibits the neointimal hyperplasia. VSMC in some pathologic progresses shifts from a contractile phenotype to a synthetic phenotype simultaneously with increased proliferation and migration. Therefore, we hypothesize EphB4 inhibits vein graft neointimal hyperplasia via VSMC phenotypic modulation. We establish the mouse vena cava vein to abdominal aorta interposition model to observe the changes in expression of VSMC phenotypic genes. We apply both gain-of-function and loss-of-function approaches in vivo and in vitro to study the role of EphB4 in VSMC phenotypic modulation, and whether it's through Caveolin-1.

自体静脉搭桥是治疗下肢动脉阻塞性疾病的主要手段,移植物为了适应动脉环境,自身结构和功能发生变化,逐渐出现管壁增厚、管腔狭窄,最终导致移植物失败。目前认为静脉移植物在适应动脉环境过程中发生重塑,平滑肌细胞的增殖迁移和新生内膜增生是移植物重塑的共同通路。血管平滑肌细胞在一些病理过程中由收缩型向分泌型转变，伴随细胞增殖和迁移增加。前期研究表明,EphB4分子能抑制静脉移植物新生内膜增生。因此,我们假设EphB4通过调控移植物平滑肌细胞分化表型的转变,抑制细胞增殖和迁移,从而抑制移植物新生内膜增生。本项目通过建立小鼠下腔静脉-腹主动脉移植模型,观察静脉移植物平滑肌细胞分化表型标志物的变化;在体内和体外实验中通过增加和减少EphB4活性,研究EphB4分子在调控静脉移植物平滑肌细胞分化表型转变中的作用,并研究这一作用是否依赖Caveolin-1分子。