Functional screening identifies miRNAs with a novel function inhibiting Vascular Smooth Muscle Cell proliferation

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.