雄激素调节肺动脉高压血管重构及肺动脉平滑肌细胞增殖的机制研究

Vascular remodeling is one of pathological characteristics of Pulmonary Arterial Hypertension (PAH) while over proliferation of Pulmonary Arterial smooth muscle cells(PASMCs) is a key reason for vascular remodeling. Recent epidemiological data reports an increased incidence of PAH among females compared to males. An accumulating evidence shows that sex steroid may explain the sex-difference. There are a mount of experiments on exploring the effect of estrogen on PAH. however, There is a paucity of data on male hormones in the pulmonary vasculature and the exact role of androgens in the physiology and pathophysiology in PAH remains uncertain. Bone morphogenetic proteins receptor 2 (BMPR2) gene mutations and down-regulation was correlated with the physiology and pathophysiology in PAH, which was more obvious in female, but the mechanismwas still unknown. So we hypothesized that androgen can alleviate vascular remodeling and then decrease pulmonary vascular resistence via AR and upregulation of BMPR2 expression. With animal model and molecular biology technique,the present study is designed to investigate the crucial role of androgen in regulating PASMCs proliferation and vascular remodeling in PAH. Furthermore, we aim to uncover the underlying mechanism and reveal the function of AR and its relation with BMPR2. Our results will be helpful to reveal the pathogenesis of PAH and afford new evidences for searching new target in treatment and prevention of PAH.

血管重构是肺动脉高压（PAH）的主要病理特征之一，肺动脉平滑肌细胞（PASMCs）过度增殖是引起肺血管重构的关键原因。近期流行病学研究提示成年女性PAH发病率明显高于男性，目前普遍研究认为该差异可能与性激素作用有关。然而，目前研究多集中于雌激素，雄激素的相关效应和机制尚缺乏报道。骨形成蛋白受体2(BMPR2) 基因突变和表达下调参与肺动脉高压发生和发展，该现象在女性中更为明显，然而其机制尚不明确。因此我们假设雄激素可通过激活雄激素受体上调BMPR2表达，缓解血管重构和降低肺阻力。本研究将从动物模型和细胞分子水平探讨雄激素对肺动脉高压大鼠血管重构和PASMCs 细胞增殖的作用，进一步揭示雄激素受体的介导效应及其与BMPR2的关系。研究结果将有助于揭示肺动脉高压发病性别差异的机制，并为发现新的肺动脉高压治疗靶点，开发特异性治疗药物提供实验依据。

血管重构是血管重构是血管结构发生改变的主动过程，是心、脑、肺等血管疾病的病理生理基础，对揭示血管性疾病病理机制和治疗策略的新变化有重要意义，逆转血管重构和预防并发症发生已成为血管生物学的研究热点。我们的研究分别从肺动脉高压和高血压病性血管重构两个点出发，探讨其可能的治疗靶点。基于肺动脉高压发病的性别差异性，我们从性激素的角度分析雄性激素对肺动脉高压血管重构的影响及可能机制。实验中我们采用野百合碱诱导的SD大鼠成模，将成模大鼠随机分为安慰剂组、去势组和雄激素替代治疗组，研究结果发现雄激素剥夺治疗可加重模型大鼠肺动脉血管重构和右心室心肌重构，引起肺动脉压力升高和右心功能恶化，该作用可能是通过雄激素受体（AR）/BMPR2途径介导的；该结论提示雄激素在肺动脉高压血管重构中可能具有保护作用，这可能是男性较女性肺动脉高压发病率低的原因之一。此外，基于肥胖在代谢性高血压的重要机制，我们研究了脂肪因子chemerin对代谢性高血压血管重构的作用及可能机制，实验中我们采用高盐高脂饮食诱导代谢性高血压大鼠模型，研究发现模型组较对照组主动脉和肠系膜上动脉血管重构更为严重，且chemerin 及其受体CMKLR1表达、自噬相关蛋白 LC3及Beclin-1表达均显著上调，提示chemerin/ CMKLR1及细胞自噬可能参与代谢性高血压血管重构过程；该结论在细胞实验中得到了证实，我们结果发现人重组chemerin蛋白可促进主动脉平滑肌细胞增殖、迁移并上调自噬表达，而该作用可被自噬抑制剂3-MA可抑制该作用；该结论提示chemerin参与代谢性高血压血管重构，而自噬可调控该效应，该结论可能成为高血压性血管重构的治疗靶点。