Abstract
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.
Highlights
Aging is an important risk factor for atherosclerotic cardiovascular diseases
Treatment with miR130a mimic restored the number and the angiogenic activities of pro-angiogenic cells (PACs) in older mice (Figure 5A–5E). This is the first report demonstrating the important role of a microRNA for the modulation of both endothelial cell senescence and the physiological response to tissue ischemia in the context of aging
Another example is patients suffering www.aging-us.com from acute myocardial infarction, in which aging has been associated with reduced collateral artery development [21]
Summary
Aging is an important risk factor for atherosclerotic cardiovascular diseases. Advanced atherosclerosis in the elderly is likely to manifest irreversible changes, including severe and diffuse obstructive lesions leading to impaired tissue perfusion. The capacity of the organism to grow new blood vessels (neovascularization) represents an important adaptive mechanism to prevent ischemia [1]. Neovascularization is classically linked to angiogenesis, which is defined as the proliferation and migration of mature endothelial cells leading to extension of a pre-existing vascular network [2]. Postnatal neovascularization is regulated by the activities of bone marrow-derived pro-angiogenic cells (PACs) [3, 4]. PACs are incorporated into ischemic tissues where they stimulate neovascularization mainly through paracrine secretion of growth factors and cytokines [5]
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