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Old 08-29-2018, 06:54 AM
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rss Mechano Growth Factor - Exposure of Endothelium to Biomimetic Flow Waveforms Yields I

Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis.

Mol Ther Nucleic Acids. 2018 Aug 08;12:829-844

Authors: Heuslein JL, Gorick CM, McDonnell SP, Song J, Annex BH, Price RJ

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 (IKK?, 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.


PMID: 30153567 [PubMed - as supplied by publisher]



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