Remote physiological ischemic training promotes coronary angiogenesis via molecular and cellular mobilization after myocardial ischemia.

Abstract

This study was designed to explore the mechanism of physiological ischemic training (PIT) on remote limbs, with a special focus on the potential role of endothelial progenitor cells (EPCs), vascular endothelial growth factor (VEGF), and nitric oxide (NO) in local ischemic myocardium. Myocardial ischemia (MI) rabbit models were randomly assigned to sham-operated group (SO), training-only group (TO), MI group, PIT group, VEGF inhibitor group (VEGF-), NO inhibitor group (NO-), VEGF and NO inhibitor group (VEGF-/NO-), and EPC inhibitor group (EPC-). A constrictor was implanted around the left ventricular branch to induce controlled MI. The PIT procedure consisted of three cycles of a 3-minutes cuff inflation on the hindlimbs with a reperfusion of 5minutes. Plasma and myocardial EPC numbers, VEGF level, and NO concentration, as well as capillary density (CD), coronary blood flow (CBF), and coronary collateral blood flow (CCBF) in myocardium, were measured. Nonparametric statistical techniques were applied to identify the differences between groups, and regression models were used to detect correlations between agents. VEGF levels, NO concentrations, and also EPC counts in both plasma and myocardium were highest in the PIT group. Capillary density, CCBF, and CCBF/CBF were also statistically elevated in the PIT group. VEGF explained 74% of variance in NO. NO explained 65% of variance in EPCs. EPCs explained 68% of variance in capillary density. Capillary density explained 78% of variance in CCBF and CCBF/CBF. PIT mobilized EPCs and promoted revascularization through upregulating VEGF and NO level.