Research Paper Volume 12, Issue 11 pp 10180—10193
Reduced expression of microRNA-130a promotes endothelial cell senescence and age-dependent impairment of neovascularization
- 1 Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM), Research Center Montréal, Montréal, Québec Canada
Received: November 24, 2019 Accepted: May 18, 2020 Published: May 26, 2020https://doi.org/10.18632/aging.103340
How to Cite
Copyright © 2020 Dhahri et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Aging is associated with impaired neovascularization in response to ischemia. MicroRNAs are small noncoding RNAs emerging as key regulators of physiological and pathological processes. Here we investigated the potential role of microRNAs in endothelial cell senescence and age-dependent impairment of neovascularization. Next generation sequencing and qRT-PCR analyses identified miR-130a as a pro-angiogenic microRNA which expression is significantly reduced in old mouse aortic endothelial cells (ECs). Transfection of young ECs with a miR-130a inhibitor leads to accelerated senescence and reduced angiogenic functions. Conversely, forced expression of miR-130a in old ECs reduces senescence and improves angiogenesis. In a mouse model of hindlimb ischemia, intramuscular injection of miR-130a mimic in older mice restores blood flow recovery and vascular densities in ischemic muscles, improves mobility and reduces tissue damage. miR-130a directly targets antiangiogenic homeobox genes MEOX2 and HOXA5. MEOX2 and HOXA5 are significantly increased in the ischemic muscles of aging mice, but forced expression of miR-130a reduces the expression of these factors. miR-130a treatment after ischemia is also associated with increased number and improved functional activities of pro-angiogenic cells (PACs). Forced expression of miR-130a could constitute a novel strategy to improve blood flow recovery and reduce ischemia in older patients with ischemic vascular diseases.
DFR: doppler flow ratios; ECs: endothelial cells; eNOS: endothelial nitric oxide synthase; HUVECs: human umbilical vein endothelial cells; MAECs: Mouse aortic endothelial cell; miRNAs or miRs: micro RNAs; NGS: Next generation sequencing; PACs: pro-angiogenic cells; RPM: reads per million reads mapped; VEGF: vascular endothelial growth factor.