Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China.
LBCMCP, ×tégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France.
Cell Death Dis. 2019 Nov 7;10(11):853. doi: 10.1038/s41419-019-2087-y.
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)O in 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.
肝肺综合征（HPS）是肝脏疾病背景下一种严重的血管并发症。肝脏产生的因子对于调节 HPS 发病机制中的肺血管生成至关重要；然而，肺血管生成的发病机制尚未完全阐明。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）在调节血管生成中的作用。我们发现 HEs 可显著增强 PMVEC 的增殖、迁移和管腔形成。我们进一步鉴定出与 SEs 相比，HEs 中 miR-194 是明显增加的 miRNA。一旦释放，肝细胞来源的外泌体 miR-194 被 PMVEC 内化，通过直接靶向 THBS1、STAT1 和 LIF，促进 PMVEC 的增殖、迁移和管腔形成。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)O 呈正相关。因此，我们的研究结果强调了外泌体/miR-194 轴在肺血管生成中的关键病理作用，代表了 HPS 的一个新的治疗靶点。
