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Hepatocyte-derived exosomal MiR-194 activates PMVECs and promotes angiogenesis in hepatopulmonary syndrome.

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.

SUBMITTER: Chen L

PROVIDER: S-EPMC6838168 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Hepatocyte-derived exosomal MiR-194 activates PMVECs and promotes angiogenesis in hepatopulmonary syndrome.

Chen Lin L Han Yi Y Li Yujie Y Chen Bing B Bai Xuehong X Belguise Karine K Wang Xiaobo X Chen Yang Y Yi Bin B Lu Kaizhi K

Cell death & disease 20191107 11

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, ...[more]

PMID: 31700002

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Project description:Infiltration by dendritic cells (DCs) is markedly increased in the infarcted area following myocardial infarction (MI), and DC ablation has been shown to impair angiogenesis in mice post?MI. Exosomes (EXs) have long been known to act as messengers between cells; however, whether EXs derived from DCs can enhance myocardial angiogenesis post?MI remains unknown. The aim of the present study was to elucidate whether EXs derived from DCs induce myocardial angiogenesis via paracrine signaling post?MI. In vitro, suspensions of mouse bone marrow?derived DCs (BMDCs) were incubated with the supernatant of necrotic or normal cultured HL?1 myocardial cells (as the MI or control group, respectively) for 24 h. EXs isolated from the supernatant of BMDCs were termed DEXs, which were added to primary cultures of rat cardiac microvascular endothelial cells (CMECs), and angiogenesis was evaluated by measuring tube formation and vascular endothelial growth factor (VEGF) expression. In vivo, different groups of DEXs were injected into the infarcted myocardium of MI model mice. Then, angiogenesis was evaluated by measuring the number of vessels and the expression of VEGF and CD31 in the infarcted myocardium using immunohistochemistry. Moreover, the expression profile of microRNAs (miRNAs or miRs) in splenic DCs of MI model mice was analyzed by Affymetrix miRNA 4.0 chip assays, then certified in DEXs by reverse transcription?quantitative PCR analysis. Finally, miRNA?loaded DEXs were used to induce tube formation by CMECs and angiogenesis in MI model mice. It was observed that, compared with the control group, DEXs from the MI group significantly upregulated the expression of VEGF in CMECs, enhanced tube formation by CMECs, and upregulated the expression of VEGF and CD31 in the infarcted myocardium of MI model mice. miR?494?3p and miR?16a?5p, which are associated with angiogenesis, were significantly upregulated in splenic DCs of MI model mice by Affymetrix miRNA 4.0 chip assays, miR?494?3p was significantly upregulated and highly enriched in DEXs from the MI group compared with the control, and DEX?miR?494?3p enhanced tube formation by CMECs and angiogenesis in mice post?MI. These results suggest that miR?494?3p may be secreted from DCs via EXs and promotes angiogenesis post?MI. These findings indicate a novel DEX?based approach to the treatment of MI.

Project description:Background: By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into exosomes and are implicated in different aspects of tumour angiogenesis. However, the underlying mechanisms are incompletely understood. Methods: The GEPIA database and in situ hybridization assay were used to analyse expression of miR-205 in ovarian tissues. Immunohistochemistry was performed to examine the relationship between miR-205 and microvessel density. Expression of circulating miR-205 was evaluated by RT-PCR and GEO database analysis. Co-culture and exosome labelling experiments were performed to assess exosomal miR-205 transfer from ovarian cancer (OC) cells to endothelial cells ECs. Exosome uptake assays were employed to define the cellular pathways associated with the endocytic uptake of exosomal miR-205. The role of exosomal miR-205 in angiogenesis was further investigated in vivo and in vitro. Western blotting and rescue experiments were applied to detect regulation of the PTEN-AKT pathway by exosomal miR-205 in ECs. Results: miR-205 was up-regulated in OC tissues, and high expression of miR-205 was associated with metastatic progression in OC patients. Moreover, miR-205 was highly enriched in cancer-adjacent ECs, and up-regulation of miR-205 correlated positively with high microvessel density in OC patients. Importantly, miR-205 was markedly enriched in the serum of OC patients, and a high level of miR-205 in circulating exosomes was associated with OC metastasis. In addition, OC-derived miR-205 was secreted into the extracellular space and efficiently transferred to adjacent ECs in an exosome-dependent manner, and the lipid raft-associated pathway plays an important role in regulating uptake of exosomal miR-205. Exosomal miR-205 from OC cells significantly promoted in vitro angiogenesis and accelerated angiogenesis and tumour growth in a mouse model. Furthermore, we found that exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway. Conclusion: These findings demonstrate an exosome-dependent mechanism by which miR-205 derived from cancer cells regulates tumour angiogenesis and implicate exosomal miR-205 as a potential therapeutic target for OC.

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Hepatocyte-derived exosomal MiR-194 activates PMVECs and promotes angiogenesis in hepatopulmonary syndrome.

Publications

Hepatocyte-derived exosomal MiR-194 activates PMVECs and promotes angiogenesis in hepatopulmonary syndrome.

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