Origins of heterogeneity in tissue perfusion and metabolism

Abstract

In the heart and other tissues, perfusion and metabolic activity are heterogeneous and spatially correlated. The goal of this work is to investigate the causes of this behaviour. Theoretical simulations are used to examine the effects on flow distribution and oxygen levels in terminal vascular beds of inherent irregularity in network structure, considering structural adaptation of vessel diameters to haemodynamic and metabolic stimuli, and adaptation of oxygen demand to local oxygen availability. A mathematical model based on experimentally observed microvascular network structures (rat mesentery and m. sartorius) is used to simulate blood flow, oxygen transport, and adaptation of vessel diameters and tissue oxygen demand. Inherent geometric heterogeneities of vascular networks cause heterogeneity of blood flow and oxygen levels that cannot be eliminated by increasing metabolic sensitivity of diameter adaptation. Adaptation of oxygen demand to differences in oxygen availability causes increased oxygen extraction, implying improved functional capacity, and establishes a correlation between local oxygen demand and flow rate, as observed experimentally. Such a correlation is not predicted if the heterogeneity of oxygen demand is assumed to be an intrinsic tissue property. A central mechanism generating heterogeneous perfusion is the inevitable structural heterogeneity of terminal vascular beds, which cannot be fully compensated by structural adaptation of vessel diameters. Heterogeneity of metabolism may result from adaptation of tissue function to the heterogeneous oxygen availability. These findings are of interest for the understanding of tissue function, including the heart, and of results obtained by corresponding imaging approaches.