Abstract
Hypoxia modulates reparative angiogenesis, which is a tightly regulated pathophysiological process. MicroRNAs (miRNAs) are important regulators of gene expression in hypoxia and angiogenesis. However, we do not yet have a clear understanding of how hypoxia-induced miRNAs fine-tune vasoreparative processes. Here, we identify miR-130a as a mediator of the hypoxic response in human primary endothelial colony-forming cells (ECFCs), a well-characterized subtype of endothelial progenitors. Under hypoxic conditions of 1% O2, miR-130a gain-of-function enhances ECFC pro-angiogenic capacity in vitro and potentiates their vasoreparative properties in vivo. Mechanistically, miR-130a orchestrates upregulation of VEGFR2, activation of STAT3, and accumulation of HIF1α via translational inhibition of Ddx6. These findings unveil a new role for miR-130a in hypoxia, whereby it activates the VEGFR2/STAT3/HIF1α axis to enhance the vasoregenerative capacity of ECFCs.
Highlights
The ability of microRNAs to repress translation of numerous target mRNAs makes them powerful regulators of cell physiology.[1]
Enhancement of endothelial colony-forming cells (ECFCs) functionality induced by miR-130a in hypoxia is driven by the VEGFR2/STAT3/HIF1a axis To understand the molecular mechanism by which miR-130a enhances ECFC functionality under hypoxia, we evaluated expression of genes related to endothelial function by quantitative reverse-transcriptase polymerase chain reaction
The miR-130/301 family has been recognized as a master miRNA regulator of pulmonary hypertension, a disease driven by hypoxia, and miR-130 upregulation was confirmed in endothelial cells isolated from murine hypoxic lungs.[41]
Summary
The ability of microRNAs (miRNAs) to repress translation of numerous target mRNAs makes them powerful regulators of cell physiology.[1]. In the context of cell therapy, ECFCs face hypoxic challenges when delivered into ischemic tissues and there is evidence to suggest that their functionality is impaired by hypoxia.[14,15,16] New strategies to overcome the poor cell survival when delivered into ischemic tissue are needed to increase therapeutic efficiency of the generation ECFC cell therapies.[17]
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