Hepatocyte-derived exosomal MiR-194 activates PMVECs and promotes angiogenesis in hepatopulmonary syndrome
Hepatocyte-derived exosomal MiR-194 activates PMVECs and promotes angiogenesis in hepatopulmonary syndrome
复制标题
肝细胞源性外泌体 MiR-194 激活 PMVEC 并促进肝肺综合征中的血管生成
DOI：
10.1038/s41419-019-2087-y
复制
发表时间：
2019-11-07
影响因子：
9
通讯作者：
Lu, Kaizhi
中科院分区：
文献类型：
--
作者：
Chen, Lin;Han, Yi;Lu, Kaizhi
肝硬化综合征（HPS）是肝脏疾病的严重血管并发症。在HPS的发病机制中，由肝脏产生的因子对调节肺血管生成至关重要;然而，肺血管生成的致病机制尚未完全了解。我们研究了HPS大鼠血清外泌体（HEs）和假手术大鼠血清外泌体（SEs）在血管生成调控中的作用。我们发现，HE显着增强PMVEC增殖，迁移和管形成。我们进一步鉴定了与SE相比，miR-194是HE中最显著增加的miRNA。一旦释放，肝细胞来源的外泌体miR-194被PMVEC内化，导致通过直接靶向THBS 1、STAT 1和LIF促进PMVEC增殖、迁移和管形成。重要的是，P53抑制、外泌体分泌抑制或miR-194抑制可逆转外泌体miR-194在引发血管生成中的致病作用。此外，在HPS患者和大鼠的血清外泌体中发现高水平的miR-194，并且与P（A-a）O2正相关。因此，我们的研究结果强调了外泌体/miR-194轴在肺血管生成中起着关键的病理作用，代表了HPS的新治疗靶点。
Hepatopulmonary syndrome (HPS) is a serious vascular complication in the setting of liver disease. Factors produced by the liver are essential to regulate pulmonary angiogenesis in the pathogenesis of HPS; however, the pathogenic mechanisms of pulmonary angiogenesis are not fully understood. We investigated the role of HPS rat serum exosomes (HEs) and sham-operated rat serum exosomes (SEs) in the regulation of angiogenesis. We found that HEs significantly enhance PMVEC proliferation, migration, and tube formation. We further identified miR-194 was the most notably increased miRNA in HEs compared to SEs. Once released, hepatocyte-derived exosomal miR-194 was internalized by PMVECs, leading to the promotion of PMVEC proliferation, migration, and tube formation through direct targeting of THBS1, STAT1, and LIF. Importantly, the pathogenic role of exosomal miR-194 in initiating angiogenesis was reversed by P53 inhibition, exosome secretion inhibition or miR-194 inhibition. Additionally, high levels of miR-194 were found in serum exosomes and were positively correlated with P(A-a)O2in HPS patients and rats. Thus, our results highlight that the exosome/miR-194 axis plays a critical pathologic role in pulmonary angiogenesis, representing a new therapeutic target for HPS.