Functional Exhaustion of Bone Marrow Derived Endothelial Progenitor Cells in a Chronic Swine Model of Myocardial Ischemia

Abstract

The functional impairment of bone marrow derived endothelial progenitor cells remains an important barrier for cardiac cell-based therapies. Our aim was to create a relevant swine model of chronic ischemia and document its effect on bone derived progenitor cells. We hypothesized that bone marrow derived endothelial progenitor cells would be functionally impaired in the setting of chronic cardiac dysfunction of ischemic origin. At baseline, Landrace miniswine was instrumented with a fixed occluder to the proximal left anterior descending coronary artery. We evaluated the animals over a 3-month period (0, 45 and 90 days). Focal proximal left anterior descending stenosis was angiographically confirmed in all animals (mean diameter stenosis = 96±4%, n=12). The resulting ischemic myocardium had evidence of contractile dysfunction but preserved viability. A progressive decline in circulating levels of endothelial progenitor cells was documented 3 months following instrumentation (P<0.001). Quantitative polymerase chain reaction analysis revealed that chronic myocardial ischemia produced a biphasic response in both hypoxic-inducible factor 1 and stromal-derived factor 1 mRNA expression. While initially unregulated, a gradual decline in hypoxic-inducible factor 1 and stromal-derived factor 1 mRNA expression was observed over time (from day 45 to 90). On serial assessment, endothelial progenitor cell migration in response to chemo attractant gradients of vascular endothelial growth factor (10-200 ng/mL) and stromal cell-derived factor-1 (10-100 ng/mL) was progressively impaired. Decreased circulating levels and migratory dysfunction of bone marrow derived endothelial progenitor cells were documented in a reproducible clinically relevant model of myocardial ischemia. Our model of chronic ischemic cardiac dysfunction could contribute to improved understanding of cellular mechanisms involved in the mobilization and exhaustion of endothelial progenitor cells in patients with heart failure.