Coronary Microvessel Vasodilation Downstream of H2O2: Effects of Ischemia, Exercise Training, and Sex

Abstract

Hydrogen peroxide (H2O2) is a vasoactive signaling molecule that is implicated in the cardio-protective effects of exercise training. Exercise training increases both H2O2 production and vascular sensitivity to H2O2, which is capable of inducing vasodilation when nitric oxide bioavailability is impaired, such as in atherosclerotic coronary artery disease. To examine the impact that exercise training has on H2O2-mediated dilation of coronary arterioles in the presence of coronary ischemia, we surgically instrumented male and female Yucatan miniature swine with an ameroid occluder on the proximal left circumflex coronary artery. The ameroid occluder gradually impaired and then inhibited blood flow through the left circumflex coronary artery, creating an area of ischemia that is reliant on collateral blood flow. After recovery, pigs were assigned to a sedentary or a progressive exercise training group for 14 weeks and then assessed for coronary vascular changes. We found that in female pigs, coronary artery occlusion decreased sensitivity to H2O2 as a vasodilator, but that sensitivity was restored by exercise training. Exercise training increased the contribution of both large-conductance calcium-gated potassium (BKCa) and voltage-gated potassium (Kv) channels to H2O2-mediated vasodilation in coronary arterioles. After exercise training, we also observed a greater role for protein kinase A (PKA) in H2O2-mediated dilation and discovered that H2O2-stimulated colocalization of PKA with BKCa channels was significantly increased in collateral-dependent arteries. In contrast, colocalization of protein kinase G (PKG) and BKCa was not altered by H2O2 compared with baseline and neither occlusion nor exercise training altered the colocalization of PKG and BKCa channels. Interestingly, in male pigs, coronary artery occlusion significantly enhanced vasodilation to H2O2 in arterioles of both sedentary and exercise-trained pigs. Unlike that observed in female pigs, neither Kv nor BKCa channels contributed to H2O2-mediated dilation in male pigs. PKG dimerization was elevated after H2O2 treatment in collateral-dependent small arteries from exercise-trained males, likely mediating the increased response to H2O2. Thus, H2O2 mediates changes in coronary arteriolar vasodilation via different pathways in a sex-dependent manner after occlusion or exercise training.