平滑肌细胞（SMC）去分化（de-differentiation）是肺动脉高压血管重构的关键过程。肺动脉高压的肺血管有明显的炎症浸润，且炎症因子在导致肺血管SMC的去分化中扮演重要角色。前期实验中，我们发现CD40基因沉默可抑制炎症浸润和血管重构。为此，我们设想CD40/CD40L轴可能是介导炎症浸润的肺血管中SMC去分化的调控途径。本项目拟开展CD40/CD40L轴调控SMC去分化参与肺动脉高压血管重构的机制研究。项目内容包括：以基因沉默和不同浓度梯度CD40L干预的方法离体分析CD40/CD40L轴活性对SMC表型、功能及相关信号分子TRAFs等的影响；建立内皮--SMC共培养体系，结合缺氧+炎症微环境，模拟肺动脉高压环境分析CD40/CD40L轴在SMC的去分化中的作用及其机制；在体分析肺动脉高压大鼠中CD40/CD40L轴活性与血管重构和SMC表型、功能的关系及其调控机制。

The de-differentiation of smooth muscle cell (SMC) is crucial to vascular remodeling for pulmonary arterial hypertension, in which there is an obvious inflammatory infiltration around the pulmonary vascular. Some concerning inflammatory factors may play an important role in SMC de-differentiation. In previous experiments of rat pulmonary hypertension models, we found that CD40 gene silencing might inhibit pulmonary vascular inflammation infiltrating and vascular remodeling. Thus, it is hypotheysized that CD40/CD40L axis may be an important way mediating pulmonary vascular SMC de-differentiation in inflammatory infiltration. The project aims to carry out the researches about CD40/CD40L axis how to control de-differentiation SMCs in pulmonary hypertension vascular remodeling. The contents include: In vitro, it is investigated that there may be changes in SMC phenotypes, functions and related signaling molecules when CD40/CD40L axis is activated or inactivated by pretreatments with sCD40L in different concentrations and CD40 gene silencing. Secondly, changes are observed in SMC phenotypes, functions, related signaling molecules with endothelial cell-SMC co-culture system and imitating microenvironment of hypoxia and inflammation. Thirdly, in pulmonary hypertension rat models, it is further confirmed that vascular remodeling and changes of SMC phenotype and relevant signal molecules are associated with CD40/CD40L axis activity. Achievement of this project will clarify the molecular mechanisms and the role of inflammation in pulmonary vascular remodeling, and provide theoretical basis for a new target of pulmonary hypertension treatment.