压力信号调控成纤维细胞活化参与低氧性肺血管重构的作用及分子机制

Hypoxia and pulmonary vascular constriction are the important causes for pulmonary vascular remodeling in hypoxia pulmonary hypertension. The activation of pulmonary artery fibroblasts (PAFs)is one of the key steps in the hypoxic remodeling of pulmonary vascular, however, its mechanism is not full known. In the previous studies we found that both hypoxia and stretchstimulation could directly activate the PAFs, but the decreased expression of lamin A/C andemerin and the increased function of β-catenin were found only in the stretch-activated PAFs. So we propose that the abnormal stretch signals,due to the hypoxia-induced constriction of pulmonary vascular, may activate PAFs via lamin A/C and emerin-associated pathways, and plays key role in the pulmonaryvascular remodeling in hypoxia pulmonary hypertension. The present project is to firstly determine the effects of lamin A/C and emerin in the stretch-induced activation of PAFs in vitro, then identify its molecular mechanism via chip-Chip and bioinformatics analysis, finally explore its role in the hypoxic remodeling of pulmonary vascular in transgene animals. The present project explores the mechanism of the activation of PAFs based on the abnormal stretch signals, so its results may afford novel information for the mechanism of pulmonary vascular remodeling and new target for the treatment of hypoxia pulmonary hypertension.

低氧和肺血管收缩肺动脉压力增高是肺血管重构的两大重要原因，肺血管外膜成纤维细胞（PAFs）活化是低氧性肺血管重构的重要环节，但其活化机制尚未完全明确。课题组前期发现：低氧和力学刺激信号均可直接活化PAFs，但只有力学信号活化PAFs同时伴有核膜蛋白lamin A/C 、emerin表达明显下降和β-catenin活性升高。因此推测：肺血管收缩引起的压力信号异常可能通过lamin A/C、emerin相关分子通路调控PAFs活化，参与HPH肺血管重构。本项目拟先明确lamin A/C 、emerin在应力改变诱导PAFs活化中的作用，再结合ChIP芯片和生物信息学等方法探讨lamin A/C 、emerin活化PAFs的分子机制；最后利用转基因动物模型探讨其在低氧性肺血管重构中的作用。从力学信号异常的角度探讨PAFs活化的机制，可能为低氧性肺血管重构的发病机制提供新认识、为其治疗提供新靶点。

低氧的直接作用和肺血管反应性收缩导致的肺动脉压力增高是肺血管重构的两大重要原因，肺血管外膜成纤维细胞（PAFs）活化是低氧性肺血管重构的重要环节，但其活化机制尚未完全明确。课题组在前期发现：低氧和力学刺激信号均可直接活化PAFs，但只有力学信号活化PAFs同时伴有核膜蛋白lamin A/C 、emerin表达明显下降和β-catenin活性升高的基础上，提出肺血管收缩引起的压力信号异常可能通过lamin A/C、emerin相关分子通路调控PAFs活化，参与HPH肺血管重构的假设。本课题从整体和细胞水平明确了应力信号改变对PAFs活化的影响；阐明了核膜蛋白lamin A/C、emerin在肺血管应力信号调控PAFs活化中的重要作用；利用生物信息学分析结合ChIP-chip、qRCR等方法初步筛选到可能直接调控PAFs活化的关键转录因子，探讨了lamin A/C、emerin调控PAFs活化的具体机制。最后还在动物水平利用转基因模型探讨其在防治HPH肺血管重构中的可能性。本研究从力学信号异常的角度探讨PAFs活化的机制，为低氧性肺血管重构的发病机制提供新认识、为其治疗提供新靶点。