肝肺综合征（HPS）治疗困难，其主要病理特征是肺内微血管扩张（IPVD）。周细胞丢失是多种微血管异常扩张的重要原因，Ang2异常升高与Ang1竞争性结合Tie2受体是周细胞丢失的重要通路，但机制不详。Cx43是维持内皮细胞与周细胞稳态的关键环节；预实验显示HPS模型肺微血管周细胞数量和Cx43活性显著减少，血清中Ang2显著升高。因此推测：病肝产生大量Ang2→竞争性结合肺Tie2→Cx43失活→肺微血管周细胞丢失→IPVD形成。本课题拟建立HPS在体模型、周细胞与内皮细胞共培养模型，用Ang1、Ang2和Ang2中和抗体以及Cx43激动剂、抑制剂、siRNA和DNA干预，WB、RT-PCR、ELISA、免疫荧光、电镜、Co-IP、质谱、点突变、活细胞信号动态追踪、光遗传学LARIAT等技术研究Ang1/Ang2失衡促周细胞丢失在IPVD中的作用和机制，以期为HPS的防治提供理论依据。

Hepatolpumonary syndrome (HPS) is difficult to cure, whose main pathological alteration is intrapulmonary microvascular dilation (IPVD). Pericytes-dropout leads to many kinds of abnormal microvascular dilation, Ang2 increase and competes with Ang1 to combine with Tie2 receptor is the most important pathway which led to pericytes-dropout, but the mechanism is unclear. Due to Cx43 reduction plays a key role in pericytes-dropout and our previous data found pulmonary pericytes and Cx43 activation were decreased and serum Ang2 was increased significantly in experimental HPS rats. Thus, we hypothesized that Ang2 highly produced in diseased liver and releases to circulation, combines to and inhibits pulmonary Tie2 activation, then leads to Cx43 inactivation, pericytes-dropout, and as a result of IPVD. ECs and pericytes co-culture model and HPS rat model will be constructed and treated with exogenous Ang1 and Ang2 protein, Ang2 neutralizing antibody, Cx43 inhibiitor, agonist, siRNA and DNA transfection. Western blot, immunofluorescence, RT-PCR, ELISA, electron microscopy, Co-IP, mass spectrometry, point mutation, living cells imaging and new optogentical tool-LARIAT will be employed in this study. The aim of this study is to clarify the role and mechanism of Ang1/Ang2 imbalance induced pericytes-dropout in IPVD, which may be a new target for HPS prevention and treatment.