Abstract
BackgroundMesenchymal stem cell-derived extracellular vesicles (EVs) appear to be a very exciting treatment option for heart disease. Here, we used a swine model of chronic myocardial ischemia to evaluate the efficacy of a less-invasive method of injection of EVs via a peripheral intravenous route.MethodsSixteen Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex (LCx) artery at age 11 weeks to induce chronic myocardial ischemia. Two weeks later, they were divided into two groups: control (CON; n = 8), and intravenous injection of EVs (EVIV; n = 8). At 18 weeks of age, animals underwent final analysis and euthanasia. The chronically ischemic myocardium (LCx territory) was harvested for analysis.ResultsIntravenous injection (IV) of EVs induced several pro-angiogenic markers such as MAPK, JNK but not Akt. Whereas IV injections of EVs decreased VEGFR2 expression and inhibited apoptotic signaling (caspase 3), they increased expression of VEGFR1 that is believed to be anti-angiogenic. Injection of EVs did not result in an increase in vessel density and blood flow when compared to the control group.ConclusionsAlthough IV injection of EVs upregulated several pro-angiogenic signaling pathways, it failed to induce changes in vascular density in the chronically ischemic myocardium. Thus, a lack of increase in vascular density at the doses tested failed to elicit a functional response in ischemic myocardium.
Highlights
Despite numerous advances in prevention, diagnosis and treatment of cardiovascular disease, ischemic heart disease continues to increase in prevalence and remains the leading cause of mortality worldwide [1]
A lack of increase in vascular density at the doses tested failed to elicit a functional response in ischemic myocardium
Metabolic parameters including glucose levels, bilirubin, protein, albumin, CRP, insulin levels, cholesterol levels (HDL, LDL, triglycerides) and fructosamine were measured via arterial blood sampling and no significant difference was seen between the groups at the time of harvest
Summary
Despite numerous advances in prevention, diagnosis and treatment of cardiovascular disease, ischemic heart disease continues to increase in prevalence and remains the leading cause of mortality worldwide [1]. There are concerns related with stem cell therapies including immune-activation causing the need for immunosuppression, cell death, lack of honing capabilities, and the need for reimplantation of new cells to achieve a long-lasting effect on myocardial ischemia [4, 5]. The need for time-intensive and invasive intra-operative harvesting for autologous stem cell transfers would be required [6]. These drawbacks make stem cell therapies a less-palatable option for much of the large population in need of cardiac revascularization. Mesenchymal stem cell-derived extracellular vesicles (EVs) appear to be a very exciting treatment option for heart disease. We used a swine model of chronic myocardial ischemia to evaluate the efficacy of a less-invasive method of injection of EVs via a peripheral intravenous route
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