Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium
We have previously shown that normoxia serum-starved extracellular vesicle (EV) therapy improves myocardial function, perfusion, and angiogenesis in a swine model of chronic myocardial ischemia. Hypoxia-modified EVs have increased abundance of anti-oxidant, pro-angiogenic, and pro-survival proteins....
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2076 |
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| author | Sharif A. Sabe Cynthia M. Xu Brittany A. Potz Akshay Malhotra Mohamed Sabra Dwight D. Harris Mark Broadwin M. Ruhul Abid Frank W. Sellke |
| author_facet | Sharif A. Sabe Cynthia M. Xu Brittany A. Potz Akshay Malhotra Mohamed Sabra Dwight D. Harris Mark Broadwin M. Ruhul Abid Frank W. Sellke |
| author_sort | Sharif A. Sabe |
| collection | DOAJ |
| description | We have previously shown that normoxia serum-starved extracellular vesicle (EV) therapy improves myocardial function, perfusion, and angiogenesis in a swine model of chronic myocardial ischemia. Hypoxia-modified EVs have increased abundance of anti-oxidant, pro-angiogenic, and pro-survival proteins. The purpose of this study is to investigate the differential effects of normoxia serum-starved EVs and hypoxia-modified EVs on myocardial function, perfusion, and microvascular density in chronically ischemic myocardium. Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs underwent intramyocardial injection of either normoxia serum-starved EVs (NOR, <i>n</i> = 10) or hypoxia-modified EVs (HYP, <i>n</i> = 7). Five weeks later, pigs were euthanized, and ischemic myocardium was harvested. Hypoxia EV treatment was associated with improved contractility compared to NOR, as well as improved capillary density, without changes in arteriolar density. There were trends towards improved perfusion at rest and during pacing in the HYP group compared to NOR. Ischemic myocardium in the HYP group had increased pro-angiogenic Akt and ERK signaling and decreased expression of anti-angiogenic markers compared to the NOR group. In the setting of chronic myocardial ischemia, hypoxia-modified EVs may enhance contractility, capillary density, and angiogenic signaling pathways compared to normoxia serum-starved EVs. |
| first_indexed | 2024-03-11T09:42:58Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:42:58Z |
| publishDate | 2023-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8d5e4e2549124925bb99a39486ba33b32023-11-16T16:52:00ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243207610.3390/ijms24032076Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic MyocardiumSharif A. Sabe0Cynthia M. Xu1Brittany A. Potz2Akshay Malhotra3Mohamed Sabra4Dwight D. Harris5Mark Broadwin6M. Ruhul Abid7Frank W. Sellke8Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USAWe have previously shown that normoxia serum-starved extracellular vesicle (EV) therapy improves myocardial function, perfusion, and angiogenesis in a swine model of chronic myocardial ischemia. Hypoxia-modified EVs have increased abundance of anti-oxidant, pro-angiogenic, and pro-survival proteins. The purpose of this study is to investigate the differential effects of normoxia serum-starved EVs and hypoxia-modified EVs on myocardial function, perfusion, and microvascular density in chronically ischemic myocardium. Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs underwent intramyocardial injection of either normoxia serum-starved EVs (NOR, <i>n</i> = 10) or hypoxia-modified EVs (HYP, <i>n</i> = 7). Five weeks later, pigs were euthanized, and ischemic myocardium was harvested. Hypoxia EV treatment was associated with improved contractility compared to NOR, as well as improved capillary density, without changes in arteriolar density. There were trends towards improved perfusion at rest and during pacing in the HYP group compared to NOR. Ischemic myocardium in the HYP group had increased pro-angiogenic Akt and ERK signaling and decreased expression of anti-angiogenic markers compared to the NOR group. In the setting of chronic myocardial ischemia, hypoxia-modified EVs may enhance contractility, capillary density, and angiogenic signaling pathways compared to normoxia serum-starved EVs.https://www.mdpi.com/1422-0067/24/3/2076extracellular vesicleshypoxia-modifiedmyocardial ischemiacoronary microcirculation |
| spellingShingle | Sharif A. Sabe Cynthia M. Xu Brittany A. Potz Akshay Malhotra Mohamed Sabra Dwight D. Harris Mark Broadwin M. Ruhul Abid Frank W. Sellke Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium International Journal of Molecular Sciences extracellular vesicles hypoxia-modified myocardial ischemia coronary microcirculation |
| title | Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium |
| title_full | Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium |
| title_fullStr | Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium |
| title_full_unstemmed | Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium |
| title_short | Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium |
| title_sort | comparative analysis of normoxia and hypoxia modified extracellular vesicle therapy in function perfusion and collateralization in chronically ischemic myocardium |
| topic | extracellular vesicles hypoxia-modified myocardial ischemia coronary microcirculation |
| url | https://www.mdpi.com/1422-0067/24/3/2076 |
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