Proliferation of vascular smooth muscle cells (vSMCs) is a crucial contributor to pathological vascular remodelling. MicroRNAs (miRNAs) are powerful gene regulators and attractive therapeutic agents. Here, we aim to systematically identify and characterise miRNAs with therapeutic potential in targeting vSMC proliferation. Using a high-throughput screening, we assessed the impact of 2042 human miRNA-mimics on vSMC proliferation and identified seven miRNAs with novel vSMC antiproliferative function: miR-323a-3p, miR-449b-5p, miR-491-3p, miR-892b, miR-1827, miR-4774-3p, miR-5681b. MiRNA-mimic treatment affects proliferation of vSMCs from different vascular beds. Focusing on vein graft failure where miRNA-based therapeutics can be applied to the graft ex vivo, we showed that these miRNAs reduced human saphenous vein SMC (HSVSMC) proliferation without toxic effect. HSVSMC transcriptomic revealed distinct set of targets for each miRNA, leading to the common down-regulation of a cell cycle gene network for all miRNAs. For miR-449b-5p, we showed that its candidate target CCND1 contributes to HSVSMC proliferation. In contrast to HSVSMC, miRNA overexpression in endothelial cells led to a limited response in terms of proliferation and transcriptomics. In an ex vivo vein organ model, overexpression of miR-323a-3p and miR-449b-5p reduced medial proliferation. Collectively, our study shows the therapeutic potential of seven miRNAs to target pathological vascular remodelling.

中文翻译：

---

功能筛选可识别具有抑制血管平滑肌细胞增殖的新功能的 miRNA。


血管平滑肌细胞 （vSMC） 的增殖是病理性血管重塑的重要因素。MicroRNA （miRNA） 是强大的基因调节因子和有吸引力的治疗剂。在这里，我们旨在系统地鉴定和表征具有靶向 vSMC 增殖治疗潜力的 miRNA。使用高通量筛选，我们评估了 2042 个人类 miRNA 模拟物对 vSMC 增殖的影响，并鉴定了 7 个具有新型 vSMC 抗增殖功能的 miRNA：miR-323a-3p、miR-449b-5p、miR-491-3p、miR-892b、miR-1827、miR-4774-3p、miR-5681b。miRNA 模拟物处理会影响来自不同血管床的 vSMCs 的增殖。专注于静脉移植失败，其中基于 miRNA 的疗法可以应用于离体移植物，我们表明这些 miRNA 减少了人隐静脉 SMC （HSVSMC） 增殖而没有毒性作用。HSVSMC 转录组学揭示了每个 miRNA 的不同靶标集，导致所有 miRNA 的细胞周期基因网络共同下调。对于 miR-449b-5p，我们发现其候选靶标 CCND1 有助于 HSVSMC 增殖。与 HSVSMC 相比，内皮细胞中的 miRNA 过表达导致增殖和转录组学方面的反应有限。在离体静脉器官模型中，miR-323a-3p 和 miR-449b-5p 的过表达减少了内层增殖。总的来说，我们的研究表明了 7 个 miRNA 靶向病理血管重塑的治疗潜力。