Abstract
Arteriogenesis, the growth of endogenous collateral arteries bypassing arterial occlusion(s), is a fundamental shear stress-induced adaptation with implications for treating peripheral arterial disease (PAD). Nonetheless, endothelial mechano-signaling during arteriogenesis is incompletely understood. Here we tested the hypothesis that a mechanosensitive microRNA, miR-199a-5p, regulates perfusion recovery and collateral arteriogenesis following femoral arterial ligation (FAL) via control of monocyte recruitment and pro-arteriogenic gene expression. We have previously shown that collateral artery segments exhibit distinctly amplified arteriogenesis if they are exposed to reversed flow following FAL in the mouse. We performed a genome-wide analysis of endothelial cells exposed to a biomimetic reversed flow waveform. From this analysis, we identified mechanosensitive miR-199a-5p as a novel candidate regulator of collateral arteriogenesis. In vitro, miR-199a-5p inhibited pro-arteriogenic gene expression (IKKβ, Cav1) and monocyte adhesion to endothelium. In vivo, following FAL in mice, miR-199a-5p overexpression impaired foot perfusion and arteriogenesis. In contrast, a single intramuscular anti-miR-199a-5p injection elicited a robust therapeutic response, including complete foot perfusion recovery, markedly augmented arteriogenesis (>3.4-fold increase in segment conductance), and improved gastrocnemius tissue composition. Finally, we found plasma miR-199a-5p to be elevated in human PAD patients with intermittent claudication compared to a risk factor control population. Through our transformative analysis of endothelial mechano-signaling in response to a biomimetic amplified arteriogenesis flow waveform, we have identified miR-199a-5p as both a potent regulator of arteriogenesis and a putative target for treating PAD.
Highlights
IntroductionMature microRNAs (miRNAs) are well recognized as key regulators of vascular remodeling.[12,13] miRNAs are $22-nt, INTRODUCTION
To this end, mature microRNAs are well recognized as key regulators of vascular remodeling.[12,13] miRNAs are $22-nt, INTRODUCTION
We sought to determine if miR-199a regulates the expression of these pro-arteriogenic genes in endothelial cells (ECs) exposed to the biomimetic shear stress waveforms
Summary
Mature microRNAs (miRNAs) are well recognized as key regulators of vascular remodeling.[12,13] miRNAs are $22-nt, INTRODUCTION. Using a genome-wide approach on cultured ECs exposed to flow waveforms biomimetic of collateral segments exhibiting moderate and amplified arteriogenesis in vivo, we first identified mechanosensitive miRNA-199a as a potential regulator of collateral arteriogenesis. We tested the hypothesis that mechanosensitive miRNA-199a regulates perfusion recovery and collateral arteriogenesis following FAL via the control of monocyte recruitment and pro-arteriogenic gene expression
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