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.
Cell Tissue Res. 2020 Dec;382(3):509-518. doi: 10.1007/s00441-020-03259-w. Epub 2020 Aug 27.
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-EXs), 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-EXs were uptaken by VSMCs dominantly through caveolin-dependent endocytosis. (2) EPC-EXs remarkably increased the ACE2 level and decreased Ang II/Ang (1-7) in VSMCs activated by Ang II, whereas EPC-EXs pretreated by proteinase A blocked this effect. (3) EPC-EXs 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-EXs augmented these effects, which were attenuated by ACE2 inhibitor (DX600). In conclusion, EPC-EXs reduced Ang II-induced VSMC phenotype change by conveying functional ACE2 to downregulate the activated NF-κB pathway.
血管平滑肌细胞 (VSMCs) 的表型转化与血管疾病有关。血管紧张素转换酶 2 (ACE2) 是一种有前景的心血管靶点，因为它能够将血管紧张素 (Ang II) 转化为 Ang (1-7)。我们的研究小组最近表明，ACE2 可以调节内皮祖细胞衍生的外泌体 (EPC-EXs) 的功能。在这里，我们研究 ACE2 是否可以影响 EPC-EXs 对 VSMCs 表型转化的作用。在与过表达 ACE2 的 EPC 释放的 EXs (EPC-EXs) 共孵育后，评估 ACE2 水平以及 Ang II/Ang (1-7)、增殖/迁移、表型基因、细胞因子和 NF-κB 水平在 VSMCs 上的变化。为了确定 EX 的摄取途径，用抑制剂预处理 VSMCs。结果发现：(1) EPC-EXs 和 EPC-EXs 主要通过网格蛋白依赖性内吞作用被 VSMCs 摄取。(2) EPC-EXs 显著增加 ACE2 水平，并降低 Ang II 激活的 VSMCs 中的 Ang II/Ang (1-7)，而用蛋白酶 A 预处理 EPC-EXs 则阻断了这种作用。(3) EPC-EXs 比 EPC-EXs 更能减少 Ang II 激活的 VSMCs 的增殖/迁移活性和细胞因子 (MCP-1、TNF-α) 分泌。(4) EPC-EXs 减弱了 Ang II 诱导的 VSMC 合成表型变化，表现为上调 calponin 和 a-SMA 的表达，下调 CRBP-1 和 MYH10 的表达，同时 NF-κB 水平降低。EPC-EXs 增强了这些作用，而 ACE2 抑制剂 (DX600) 则减弱了这些作用。总之，EPC-EXs 通过传递功能性 ACE2 来降低激活的 NF-κB 通路，从而减少 Ang II 诱导的 VSMC 表型变化。
