肺动脉高压（PAH）是一种致死性疾病，持续的肺血管收缩、广泛的肺血管重构、远端肺小动脉血栓形成以及肺血管壁硬化将导致PAH病人肺血管阻力及肺动脉压力的升高，但具体机制不明。许多研究表明内皮细胞向间充质细胞转化（EndMT）与PAH的闭塞性血管病变的形成明显相关。基于文献报道及前期研究发现敲除HIF-2α可显著下调Snail蛋白水平的表达，并且降低Snail也可下调HIF-2α的表达。我们推测：HIF-2α可能通过基因组效应从转录水平调控Snail的表达，而Snail则通过PI3K/AKt途径调控HIF-2α的表达，两者形成正反馈调节环路导致EndMT的发生。因此，本研究拟利用荧光素酶报告基因检测、EMSA、ChIP实验、MCT肺动脉高压模型及转基因敲除小鼠等方法证实HIF-2α-Snail相互调节的分子机制。为临床上以HIF-2α-Snail为调控靶点，应用相关药物治疗肺动脉高压提供帮助。

Pulmonary arterial hypertension (PAH) is a life-threatening disease. Sustained pulmonary vasoconstriction, excessive pulmonary vascular remodeling, in situ distal arterial thrombosis and increased pulmonary vascular wall stiffness result in the increase of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in patients with idiopathic, heritable and associated pulmonary arterial hypertension (PAH). EndMT has recently been linked to the formation of obliterative vascular lesions in PAH. Based on preliminary data, we found knockdown HIF-2α could decrease snail expression, and knockdown snail could also decrease HIF-2α expression. We hypothesize that HIF-2α could regulate snail in transcriptional level, and snail could also change HIF-2α expression, EndMT and HIF-2α-snail loop play a very important role in the development and progression of PAH. We will analyze HIF-2α-snail signal pathway by using silencing and overexpression techniques, knockout mice, luciferase reporter gene, EMSA and ChIP experiments, to explore EndMT and HIF-2α-snail loop in the development of PAH.