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Central Surgical Association

49th Annual Meeting

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Extracellular Vesicle Therapy Attenuates Anti-Angiogenic Signaling in Ischemic Myocardium of Swine with Metabolic Syndrome
Sharif A. Sabe, Laura A. Scrimgeour, Catherine Karbasiafshar, Ahmed Aboulgheit, Cynthia M. Xu, M. Ruhul Abid, Frank W. Sellke
Division of Cardiothoracic Surgery, Department of Surgery, Rhode Island Hospital, Brown University Warren Alpert Medical School, Brookline, Massachusetts, United States

Objective: Extracellular vesicles (EV) provide therapeutic benefit to ischemic myocardium and may be a promising treatment strategy for patients with diffuse coronary artery disease and limited surgical or catheter-based therapeutic options. Our recent studies using a porcine model of metabolic syndrome (MS) and chronic myocardial ischemia demonstrate that EV therapy improves blood flow and arteriogenesis in ischemic myocardium, though the mechanisms by which these changes occur are unclear. Anti-angiogenic proteins angiostatin and endostatin are increased in patients with diabetes. We therefore hypothesized that in the setting of MS, EV therapy would decrease anti-angiogenic signaling to mediate increased blood flow to chronically ischemic myocardium.
Methods: Yorkshire swine were fed a high fat/cholesterol diet for four weeks to induce MS, then underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs underwent an additional procedure for intramyocardial injection of either vehicle (control group, n=6) or human bone marrow-derived EVs (n=8). Five weeks later, the pigs were euthanized and left ventricular myocardial tissue in the ischemic territory was harvested. Protein expression was measured using western blot, and data was statistically analyzed via Wilcoxon rank sum test. Myocardial perfusion was measured with isotope-labeled microspheres injected prior to myocardial harvest, and correlation data was statistically analyzed using Spearman’s rank correlation coefficient.
Results: EV treatment was associated with decreased expression of the anti-angiogenic proteins angiostatin (p=0.003) and endostatin (p=0.029) in ischemic myocardium compared to the control (vehicle) group. Among EV-treated pigs, there was a significant negative correlation between relative angiostatin expression (calculated as fold change compared to control) and blood flow to ischemic myocardium (rs=-0.79, p=0.028). There was no correlation between relative endostatin expression and blood flow to ischemic myocardium (rs=-0.23, p=0.58). There were no significant differences in expression of pro-angiogenic proteins angiopoietin-1, ß-catenin, DLL4, VE-Cadherin, Tie2, and VEGF-A in ischemic myocardium of EV-treated pigs compared to the control group (see Figure).
Conclusions: In the setting of metabolic syndrome and chronic myocardial ischemia, EV therapy is associated with decreased expression of the anti-angiogenic proteins angiostatin and endostatin, which may contribute to increased blood flow to ischemic myocardium. Our ongoing studies will elucidate the molecular mechanisms by which this EV-mediated decrease in anti-angiogenic proteins improves coronary arteriogenesis and blood flow but not capillary angiogenesis in ischemic myocardium in MS.


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