This research program has developed the adult miniature swine as an experimental model of exercise training (ET) for use in the study of ET-induced coronary vascular adaptation. We have established that ET improves the capacity of the coronary vascular bed to transport nutrients to and metabolites away from cardiac myocytes. ET increases both blood flow (BF) capacity and capillary diffusion capacity. Experiments proposed for Specific Aim 1 are designed to determine if ET-induced increases in coronary transport capacity are due to increased size and/or numbers of vessels (ie, angiogenesis) and/or to altered control of BF and its distribution. Morphometric techniques will be used to measure microvascular vessel numbers and size and to estimate capillary exchange area to provide a definitive test of the angiogenesis hypothesis. To evaluate the role of altered control of BF and its distribution, a uniquely complete set of coronary transport data will be obtained. Total and regional (microspheres) coronary BF, capillary diffusion capacity (multiple-indicator dilution technique), and systemic hemodynamics will be measured in-vivo with BF autoregulation intact and during maximal vasodilation. Transport data will be interpreted with model analysis employing available models and models of coronary transport that are being developed. We have also demonstrated that ET alters the intrinsic contractile behavior of coronary arteries. Results indicate that excitation-contraction coupling is altered in coronary arteries of ET pigs. Experiments outlined for Aim 2 will use isolated segments of coronary arteries to test the hypotheses that ET alters endothelium mediated control of vascular smooth muscle (VSM) tone and/or receptor mediated control of VSM cells. The experiments described for Aim # 3 will use isolated endothelial cells (EC) and VSM cells to test the hypothesis that ET alters the regulation of intra-cellular Ca++ (Cai) in coronary ECs and/or VSM cells. Cai will be measured with fura-2 microfluorimetry. Preliminary data indicate that the control of Cai is altered in both EC's and VSM of coronary arteries from ET pigs Aim 4 will determine if these ET-induced coronary adaptations are restricted to large epicardial arteries or also present in small arteries, near resistance sized arteries and arterioles. It appears that exercise training-induced coronary vascular adaptation involves: angiogenesis, altered neurohumoral control mechanisms and changes in the intrinsic contractile characteristics of coronary arteries. Completion of the proposed research will provide a comprehensive understanding of the mechanisms involved in training-induced coronary vascular adaptation and may provide information necessary for understanding the apparent effectiveness of ET in prevention and/or treatment of coronary disease.
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