miR-126上调VEGF/AKT/mTOR信号通路促进门静脉高压症侧支血管新生的机制研究

Portal hypertension (PHT) is a common and fatal complication in patients of liver cirrhosis. Recent studies showed that angiogenesis is a new mechanism for the formation of portal-systemic collateral vessels and hyperdynamic splanchnic circulation in PHT. However, the mechanism of its occurrence and regulation is still poorly understood so far. miR-126 as a vital molecule regulates angiogenesis. Our previous study found that a marked upregulation of miR-126 in mesentery was positively correlated with the high expression of VEGFR2 and P-P70S6K (The marker of AKT/mTOR signalling), as well as the evident angiogenesis of collateral vessels and hyperdynamic circulation in PHT rats. Based on these findings, we hypothesize that the upregulation of miR-126 in target tissues may be the initiating factor, which activates VEGF/AKT/mTOR signaling by regulating its target genes and finally causes the portal-systemic collateral angiogenesis and hyperdynamic splanchnic circulation. In this project, we will investigate the role of miR-126 in the formation of PHT collateral circulation for the first time by using endothelial cells culture in vitro and different PHT rat or mice models combined with miR-126 targeted silencing methods. It will illustrate the molecular network and regulatory mechanism of miR-126 in the pathogenesis of PHT by systemic biological tools, as well as its potential translational significance in clinical PHT cases. This project will not only provide new ideas for revealing the mechanism of PHT, but also for exploring new therapeutic targets from a new viewpoint of miRNA.

门静脉高压症（PHT）是肝硬化常见且致命的并发症，新近研究表明血管新生是PHT侧支循环和血流高动力形成的新机制，迄今对其发生和调控机制仍知之甚少。miR-126是调控血管生成的重要分子，我们前期研究发现，PHT动物模型肠系膜中miR-126的表达明显增加，与VEGFR2和P-P70S6K表达上调、显著的侧支血管新生和血流高动力成正相关。基于此我们提出假说：miR-126在PHT靶组织表达上调可能为始动因素，其调控靶基因启动VEGF/AKT/mTOR通路活化，从而促进门体侧支血管新生和血流高动力的形成。本项目利用内皮细胞培养和不同PHT大小鼠模型，结合miR-126靶向沉默手段，首次研究miR-126在PHT侧支循环形成中的作用，并结合系统生物学手段，阐明miR-126调节的分子网络以及在临床转化研究中的潜在意义。本项目从miRNA这个新视点为揭示PHT演进机理和探索新的治疗靶点提供新思路。

门静脉高压症（PHT）是肝硬化常见且致命的并发症，亦是长期以来困扰着医学界的一个难题。新近研究表明血管新生是PHT侧支循环和血流高动力形成的新机制，迄今对其发生和调控机制仍知之甚少。我们通过构建大鼠肝硬化PHT模型，并靶向阻断VEGF信号通路，探索血管新生在PHT侧支循环和血流高动力形成中的作用机制。研究发现，靶向阻断VEGF信号通路可显著减弱BDL大鼠肝内胆管的反应性增生和胶原纤维的沉积，改善大鼠的肝功能，同时，明显减少了食管粘膜下曲张静脉和肠系膜微静脉的密度，提示阻断VEGF信号通路不仅可减缓肝内纤维化的进展，同时还能通过减少侧枝循环的形成对大鼠门静脉高压症有一定的改善作用。因此，靶向阻断VEGF信号通路抑制血管生成，可能是肝硬化PHT具有潜在治疗价值的新策略。此外，我们发现临床肝硬化患者的肝脏标本中EPOR+库普弗细胞（KCs）显著减少，人正常肝组织中约83.9%的CD163+KCs表达EPOR。肝缺血再灌注损伤（IRI）中，EPO可促进KCs的增殖和M2表型比例的增加，并可减轻肝IRI肝组织损伤程度及肝细胞的凋亡从而保护肝功能。但具体的分子生物学机制，仍待进一步的研究。

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