Objective: Understanding message delivery among vascular cells is essential for deciphering the intercellular communications in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression. Approach and Results: We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene KLF4 (Krüppel-like factor 4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a–induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases. Conclusions: EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.

中文翻译：

---

细胞外 MicroRNA-92a 介导内皮细胞-巨噬细胞通讯

客观的：了解血管细胞之间的信息传递对于破译心血管疾病中的细胞间通讯至关重要。MicroRNA (miR)-92a 在动脉粥样硬化易发条件下在内皮细胞 (EC) 和循环中富集。巨噬细胞是动脉粥样硬化病变中调节病变发展的主要免疫细胞。因此，我们假设，为了响应动脉粥样硬化的刺激，ECs 将 miR-92a 输出到巨噬细胞以调节其功能并促进动脉粥样硬化进展。 方法和结果：我们研究了在易发生动脉粥样硬化的微环境下 EC miR-92a 调节的巨噬细胞功能。我们首先通过从内皮条件培养基和小鼠血清中分离出泡内和泡外区室来确定功能性细胞外 miR-92a 的分布。结果表明细胞外囊泡是 EC miR-92a 运输的主要载体。EC 中 miR-92a 的过度表达增强了共培养巨噬细胞的促炎反应和低密度脂蛋白摄取，同时损害了其迁移。在与 miR-92a 敲低的 EC 共培养的巨噬细胞中发现了相反的效果。进一步分析表明，囊泡内miR-92a抑制了靶基因的表达KLF4（Krüppel 样因子 4）存在于巨噬细胞中，提示囊泡内 miR-92a 调节受体细胞功能的机制。事实上，KLF4 的过度表达挽救了 EC miR-92a 诱导的巨噬细胞易发生动脉粥样硬化的表型。此外，在动脉粥样硬化动物中观察到血清中的囊内miR-92a与病变中的KLF4表达呈负相关，表明细胞外miR-92a在调节血管疾病中的潜在功能。 结论：EC miR-92a可以通过细胞外囊泡转运至巨噬细胞来调节KLF4水平，从而导致巨噬细胞易发生动脉粥样硬化的表型，从而形成动脉粥样硬化病变。