Temporally distributed mechanisms for skeletal muscle microvascular rarefaction in metabolic syndrome (674.9)

Abstract

Evolution of metabolic syndrome (MetSyn) and its constituent pathologies is associated with a gradual reduction in skeletal muscle microvessel density (MVD), known as rarefaction. While contributing to elevated vascular resistance at high metabolic demand and impairing mass transport/exchange, the temporal development of rarefaction and the contributing mechanisms which lead to the progressive microvessel loss are critical areas for investigation. Our studies demonstrate that overall reductions to MVD in skeletal muscle of obese Zucker rats (OZR) are well predicted by a chronic loss in vascular nitric oxide (NO) bioavailability. However, prior to any loss in NO, skeletal muscle arterioles from OZR exhibit an early shift in ROS, inflammatory biomarkers and arachidonic acid metabolism, resulting in increased production of TxA2. This increases venular leukocyte adhesion and causes a second, localized oxidant pulse, which initiates microvascular degradation in post‐capillary venules that is strongly associated with plasma MCP‐1 levels. If NO bioavailability is maintained (TEMPOL) after the initial increase in TxA2 and microvessel loss, the total rarefaction magnitude is blunted. Alternately, if actions of TxA2 are chronically inhibited, the initial rarefaction never develops and the subsequent secondary pulse (from NO reductions) is strongly muted. A similar muting of the initial and secondary pulse of rarefaction is manifested if TNF‐α production is inhibited (pentoxifyllene). These results suggest that microvessel rarefaction in OZR represents the integration of an early mild vessel loss that is dependent on TxA2, which creates an environment for the extensive rarefaction that is dependent on low NO bioavailability.Grant Funding Source: Supported by National Institutes of Health and American Heart Association