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Angiotensin-converting enzyme 2 augments the effects of endothelial progenitor cells–exosomes on vascular smooth muscle cell phenotype transition

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Abstract

Phenotype transition of vascular smooth muscle cells (VSMCs) is implicated in vascular diseases. Angiotensin-converting enzyme 2 (ACE2) is a perspective cardiovascular target due to its ability of converting angiotensin (Ang II) to Ang (1–7). Our group recently showed that ACE2 can regulate the function of endothelial progenitor cell–derived exosomes (EPC-EXs). Here, we investigate whether ACE2 could affect the role of EPC-EXs on phenotype transition of VSMCs. After co-incubation with EXs released from EPC overexpressed ACE2 (EPC-EXsACE2), the ACE2 level and Ang II/Ang (1–7), proliferation/migration, phenotype gene, cytokine and NF-κB level on VSMCs were assessed. To determine the EX uptake route, VSMCs were pretreated with inhibitors. We found that (1) EPC-EXs and EPC-EXsACE2 were uptaken by VSMCs dominantly through caveolin-dependent endocytosis. (2) EPC-EXsACE2 remarkably increased the ACE2 level and decreased Ang II/Ang (1–7) in VSMCs activated by Ang II, whereas EPC-EXsACE2 pretreated by proteinase A blocked this effect. (3) EPC-EXsACE2 had better effects than EPC-EXs on reducing proliferation/migration activities and cytokine (MCP-1, TNF-α) secretion of Ang II–activated VSMCs. (4) EPC-EXs attenuated Ang II–induced VSMC synthetic phenotype change as evidenced by upregulated expressions of calponin and a-SMA and downregulated expressions of CRBP-1 and MYH10, associated with a decreased NF-κB level. EPC-EXsACE2 augmented these effects, which were attenuated by ACE2 inhibitor (DX600). In conclusion, EPC-EXsACE2 reduced Ang II–induced VSMC phenotype change by conveying functional ACE2 to downregulate the activated NF-κB pathway.

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Funding

This work is supported by the National Natural Science Foundation of China (31701026, 81873474 and the Science and Techonology Program of Guangzhou, China (202002030336)).

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  1. Jinju Wang and Jiao Li contributed equally to this work.

Authors and Affiliations

  1. Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Disease, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China

    Jinju Wang, Jiao Li, Chuanfang Cheng & Shiming Liu

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  1. Jinju Wang
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  2. Jiao Li
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  3. Chuanfang Cheng
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  4. Shiming Liu
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Correspondence to Shiming Liu.

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Wang, J., Li, J., Cheng, C. et al. Angiotensin-converting enzyme 2 augments the effects of endothelial progenitor cells–exosomes on vascular smooth muscle cell phenotype transition. Cell Tissue Res 382, 509–518 (2020). https://doi.org/10.1007/s00441-020-03259-w

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