Microvascular perfusion heterogeneity impairs oxygenation and contributes to peripheral vascular disease in metabolic syndrome

Abstract

It has been established that development of the metabolic syndrome in obese Zucker rats (OZR) is associated with impaired fatigue-resistance of in situ skeletal muscle paralleling a blunted functional hyperemia. However, recent studies suggest that reduced bulk oxygen delivery to skeletal muscle with elevated metabolic demand is not sufficient to explain the compromised muscle performance. Using novel experimental data and recent insight into altered perfusion within the microcirculation of OZR, we developed a new simulation for tissue oxygenation with increasing metabolic demand in lean (LZR) and OZR skeletal muscle using physiologically-realistic data and relationships. As metabolic demand rose (via contraction frequency), blood flow to, and oxygen uptake by, in situ skeletal muscle increased in both strains, although the response was blunted in OZR. Oddly, venous blood oxygen tension (PvO2) draining the gastrocnemius muscle of OZR was elevated versus LZR across metabolic demands; a paradoxical response given assumptions of incrased microvascular residency time in skeletal muscle of OZR. Using a microvascular network model of multiple Krogh cylinders supplied by a network with homogeneous flow distribution at bifurcations (gamma=0.5), we were unable to simulate tissue oxygenation and PvO2 differences between LZR and OZR. However, with introduction of increasing perfusion asymmetry (gamma>0.5), changes to microvascular hematocrit and increased plasma skimming throughout the network, our ability to simulate the experimental results was much improved. As a result, we have demonstrated that increased perfusion asymmetry (gamma) within the skeletal muscle microcirculation is not only a defining characteristic of the metabolic syndrome, it is required to effectively model and understand alterations in blood-tissue oxygen exchange in this highly translationally relevant model of human disease risk