de Yebenes, Virginia GBriones, Ana MMartos-Folgado, InmaculadaMur, Sonia M.Oller, JorgeBilal, FaizGonzález-Amor, MaríaMendez-Barbero, NereaSilla-Castro, Juan CarlosWere, FelipeJimenez-Borreguero, Luis JSanchez-Cabo, FatimaBueno, HectorSalaices, MercedesRedondo, Juan MiguelRamiro, Almudena R2021-06-232021-06-232020-10Arterioscler Thromb Vasc Biol. 2020; 40(10):2408-24241524-4636http://hdl.handle.net/20.500.12105/13177microRNAs are master regulators of gene expression with essential roles in virtually all biological processes. miR-217 has been associated with aging and cellular senescence, but its role in vascular disease is not understood. Approach and Results: We have used an inducible endothelium-specific knock-in mouse model to address the role of miR-217 in vascular function and atherosclerosis. miR-217 reduced NO production and promoted endothelial dysfunction, increased blood pressure, and exacerbated atherosclerosis in proatherogenic apoE-/- mice. Moreover, increased endothelial miR-217 expression led to the development of coronary artery disease and altered left ventricular heart function, inducing diastolic and systolic dysfunction. Conversely, inhibition of endogenous vascular miR-217 in apoE-/- mice improved vascular contractility and diminished atherosclerosis. Transcriptome analysis revealed that miR-217 regulates an endothelial signaling hub and downregulates a network of eNOS (endothelial NO synthase) activators, including VEGF (vascular endothelial growth factor) and apelin receptor pathways, resulting in diminished eNOS expression. Further analysis revealed that human plasma miR-217 is a biomarker of vascular aging and cardiovascular risk. Our results highlight the therapeutic potential of miR-217 inhibitors in aging-related cardiovascular disease.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Plaque, AtheroscleroticAge FactorsAttribution-NonCommercial-NoDerivatives 4.0 Internacional3284738840102408-242410.1161/ATVBAHA.120.314333Arteriosclerosis, thrombosis, and vascular biologyopen access