Abstract
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)O2 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.
Highlights
Hepatopulmonary syndrome (HPS) is a progressive disease that is characterized by worsening hypoxemia due to intrapulmonary vascular dilatation (IPVD), arteriovenous malformations and increased angiogenesis in the setting of chronic liver disease[1,2,3]
To explore the changes of serum exosomes in the HPS model, HPS was induced by common bile duct ligation (CBDL) as previously reported[28]
An increasing number of studies have identified that angiogenesis caused by angiogenic factors plays an important role in HPS50,51
Summary
Hepatopulmonary syndrome (HPS) is a progressive disease that is characterized by worsening hypoxemia due to intrapulmonary vascular dilatation (IPVD), arteriovenous malformations and increased angiogenesis in the setting of chronic liver disease[1,2,3]. Over the past two decades, the pathogenesis and precise mechanisms of HPS have been under active investigation. Exosomes can shuttle bioactive molecules, Official journal of the Cell Death Differentiation Association. It is interesting and important to explore whether exosomes are involved in and critical to HPS.
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