Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253118302051 |
| _version_ | 1818446320259563520 |
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| author | Joshua L. Heuslein Catherine M. Gorick Stephanie P. McDonnell Ji Song Brian H. Annex Richard J. Price |
| author_facet | Joshua L. Heuslein Catherine M. Gorick Stephanie P. McDonnell Ji Song Brian H. Annex Richard J. Price |
| author_sort | Joshua L. Heuslein |
| collection | DOAJ |
| description | 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. Keywords: endothelial, microRNA, miR-199a-5p, peripheral arterial disease, femoral arterial ligation, hindlimb ischemia, shear stress |
| first_indexed | 2024-12-14T19:45:51Z |
| format | Article |
| id | doaj.art-f895f5623979446499e767c05a1f0ac1 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-14T19:45:51Z |
| publishDate | 2018-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-f895f5623979446499e767c05a1f0ac12022-12-21T22:49:34ZengElsevierMolecular Therapy: Nucleic Acids2162-25312018-09-0112829844Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of ArteriogenesisJoshua L. Heuslein0Catherine M. Gorick1Stephanie P. McDonnell2Ji Song3Brian H. Annex4Richard J. Price5Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USADepartment of Biomedical Engineering, University of Virginia, Charlottesville, VA, USARobert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USADepartment of Biomedical Engineering, University of Virginia, Charlottesville, VA, USARobert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USADepartment of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA; Corresponding author: Richard J. Price, PhD, Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, VA 22903, USA.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. Keywords: endothelial, microRNA, miR-199a-5p, peripheral arterial disease, femoral arterial ligation, hindlimb ischemia, shear stresshttp://www.sciencedirect.com/science/article/pii/S2162253118302051 |
| spellingShingle | Joshua L. Heuslein Catherine M. Gorick Stephanie P. McDonnell Ji Song Brian H. Annex Richard J. Price Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis Molecular Therapy: Nucleic Acids |
| title | Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis |
| title_full | Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis |
| title_fullStr | Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis |
| title_full_unstemmed | Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis |
| title_short | Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis |
| title_sort | exposure of endothelium to biomimetic flow waveforms yields identification of mir 199a 5p as a potent regulator of arteriogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2162253118302051 |
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