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.

中文翻译：

---

血管紧张素转换酶 2 增强内皮祖细胞-外泌体对血管平滑肌细胞表型转变的影响

血管平滑肌细胞 (VSMC) 的表型转变与血管疾病有关。血管紧张素转化酶 2 (ACE2) 是一个潜在的心血管靶点，因为它能够将血管紧张素 (Ang II) 转化为 Ang (1-7)。我们小组最近表明 ACE2 可以调节内皮祖细胞衍生的外泌体 (EPC-EX) 的功能。在这里，我们研究 ACE2 是否会影响 EPC-EXs 在 VSMCs 表型转变中的作用。与 EPC 过表达的 ACE2 (EPC-EXsACE2) 释放的 EX 共孵育后，评估 VSMC 上的 ACE2 水平和 Ang II/Ang (1-7)、增殖/迁移、表型基因、细胞因子和 NF-κB 水平。为了确定 EX 摄取途径，用抑制剂预处理 VSMC。我们发现 (1) EPC-EXs 和 EPC-EXsACE2 主要通过小窝蛋白依赖性内吞作用被 VSMCs 吸收。(2) EPC-EXsACE2 显着增加了 Ang II 激活的 VSMC 中 ACE2 水平并降低了 Ang II/Ang (1-7)，而蛋白酶 A 预处理的 EPC-EXsACE2 阻止了这种作用。(3) EPC-EXsACE2在降低Ang II激活的VSMCs的增殖/迁移活性和细胞因子（MCP-1，TNF-α）分泌方面比EPC-EXs具有更好的效果。(4) EPC-EXs 减弱了 Ang II 诱导的 VSMC 合成表型变化，如钙调蛋白和 a-SMA 的上调表达以及 CRBP-1 和 MYH10 的下调表达所证明的，与降低的 NF-κB 水平相关。EPC-EXsACE2 增强了这些作用，而 ACE2 抑制剂 (DX600) 会减弱这些作用。总之，EPC-EXsACE2 通过传递功能性 ACE2 下调激活的 NF-κB 通路来减少 Ang II 诱导的 VSMC 表型变化。