TEMPORAL PROGRESSION OF MICROVASCULAR RAREFACTION IN THE METABOLIC SYNDROME

The metabolic syndrome (MS) represents an integrated, multifaceted disease state wherein multiple pathologies result in a synergistically negative outcome. A significant outcome of these pathologies is a progressive loss of skeletal muscle microvessel density (rarefaction) resulting in inadequacies in demand/perfusion matching. We sought to determine the mechanisms and temporal progression of skeletal muscle rarefaction. Mean arterial pressure, changes in which were thought to be associated with rarefaction, was found to be a poor predictor of microvessel loss. Nitric oxide (NO) bioavailability, however, demonstrated itself to be a powerful predictor of microvessel density. The loss of NO bioavailability and resultant rarefaction could be blunted but not abolished by chronic antioxidant (TEMPOL) treatment. The significance of NO bioavailability was recapitulated as exercise protected against both rarefaction and loss of NO. Temporal analyses found that rarefaction is a biphasic process and, while NO is still a robust predictor of density, there is an early phase of rarefaction for which NO has no predictive value. This early phase, which is apparently mediated by elevations in thromboxane A2 levels, appears to be initiated by changes in oxidative stress and inflammatory profile. Taken together these data demonstrate that rarefaction is a dynamic, multi‐phase process mediated by disparate factors.