TUMOR NECROSIS FACTOR ALPHA CONTRIBUTES TO VASCULAR DYSFUNCTION AND SKELETAL MUSCLE MICROVASCULAR RAREFACTION IN THE OBESE ZUCKER RAT

Accompanying the progression of the metabolic syndrome is the development of a chronic, low level inflammatory state. Previous studies from our group have demonstrated that an early contributor to this obesity‐related inflammatory condition is the cytokine tumor necrosis factors‐alpha (TNFα). We sought to chronically inhibit TNFα synthesis through administration of pentoxifylline in obese Zucker rats, a genetically hyperphagic model of the metabolic syndrome. Animals receiving this therapy from 7 to 20 weeks of age demonstrated improvements to skeletal muscle microvessel density (~75% reduction in rarefaction) as well as increased vascular responsiveness to endothelium‐dependent dilator stimuli (acetylcholine and hypoxia) while also demonstrating diminished production of the constrictor prostanoid thromboxane A2 (~30%). Despite partially protecting against the increase in oxidant stress that has been documented with metabolic syndrome, vascular wall mechanics were still impaired in treated animals. These results suggest that TNFα serves in the progression of metabolic syndrome vascular symptomologies through deleterious effects on both vasomotor function and vascular network structure in the skeletal muscle microvasculature whereas the alterations to wall mechanics occur via a mechanism independent of TNFα mediated effects.