Capillary module haemodynamics and mechanisms of blood flow regulation in skeletal muscle capillary networks: Experimental and computational analysis.

The capillary module (CM), consisting of parallel capillaries from terminal arteriole to post-capillary venule, is classically considered to be the building block of complex capillary networks. In skeletal muscle, CMs form interconnected columns spanning thousands of microns, which we recently described as the capillary fascicle. However, detailed evaluation of CM haemodynamics has not been described, and may provide insight into mechanisms of blood flow regulation in the microcirculation. We used intravital videomicroscopy from resting extensor digitorum longus muscle in rats (n = 9 networks, 112 capillary modules), as well as dual-phase computational modelling of blood flow in simulated CM geometries. We found that the mean driving pressure across CMs was 3.236 ± 1.833 mmHg. Red blood cell (RBC) flow was independent of CM resistance, and the ratio of blood flow in adjacent modules was not correlated with their ratio of resistances. In simulated CM geometries, increases to driving pressure produced a direct linear increase to RBC and plasma flow, with no changes to RBC distribution; increases to arteriolar inflow haematocrit resulted in increased RBC flow, but with viscosity-dependent increases to CM resistance. CM RBC flow heterogeneity was higher than plasma flow heterogeneity in experimental data, in contrast to simulated geometries, suggesting that time-dependent flow variability may have important consequences for RBC distribution. In summary, these findings suggest that CMs are active participants in microvascular flow regulation, likely achieved through adjustments to CM driving pressure using pre- and post-capillary loci of flow control. Increases to CM viscosity may be important during the regulation of functional hyperaemia. KEY POINTS: The capillary module (CM), consisting of parallel capillaries from the arteriole to venule, is classically considered to be the building block of capillary networks in skeletal muscle. A detailed evaluation of module haemodynamics may provide insight into mechanisms of blood flow regulation in the microcirculation. Using experimental data from resting skeletal muscle in rats, as well as dual-phase computational models of blood flow, we analysed haemodynamic relationships and the impact of variations to boundary conditions on red blood cell and plasma distribution. We showed that driving pressure across CMs is low, and that simulated increases to inflow haematocrit have important viscosity-dependent effects on module resistance. We found that red blood cell flow was independent from module resistance, which strongly suggests the regulation of driving pressure at the level of the capillary module using pre- and post-capillary loci of flow control. These findings place CMs as central participants in microvascular flow regulation, with important consequences for disease and functional hyperaemia.

The capillary fascicle in skeletal muscle: Structural and functional physiology of RBC distribution in capillary networks.

KEY POINTS: The capillary module, consisting of parallel capillaries from arteriole to venule, is classically considered as the building block of complex capillary networks. In skeletal muscle, this structure fails to address how blood flow is regulated along the entire length of the synchronously contracting muscle fibres. Using intravital video microscopy of resting extensor digitorum longus muscle in rats, we demonstrated the capillary fascicle as a series of interconnected modules forming continuous columns that align naturally with the dimensions of the muscle fascicle. We observed structural heterogeneity for module topology, and functional heterogeneity in space and time for capillary-red blood cell (RBC) haemodynamics within a module and between modules. We found that module RBC haemodynamics were independent of module resistance, providing direct evidence for microvascular flow regulation at the level of the capillary module. The capillary fascicle is an updated paradigm for characterizing blood flow and RBC distribution in skeletal muscle capillary networks. ABSTRACT: Capillary networks are the fundamental site of oxygen exchange in the microcirculation. The capillary module (CM), consisting of parallel capillaries from terminal arteriole (TA) to post-capillary venule (PCV), is classically considered as the building block of complex capillary networks. In skeletal muscle, this structure fails to address how blood flow is regulated along the entire length of the synchronously contracting muscle fibres, requiring co-ordination from numerous modules. It has previously been recognized that TAs and PCVs interact with multiple CMs, creating interconnected networks. Using label-free intravital video microscopy of resting extensor digitorum longus muscle in rats, we found that these networks form continuous columns of linked CMs spanning thousands of microns, herein denoted as the capillary fascicle (CF); this structure aligns naturally with the dimensions of the muscle fascicle. We measured capillary-red blood cell (RBC) haemodynamics and module topology (n = 9 networks, 327 modules, 1491 capillary segments). The average module had length 481 µm, width 157 µm and 9.51 parallel capillaries. We observed structural heterogeneity for CM topology, and functional heterogeneity in space and time for capillary-RBC haemodynamics within a module and between modules. There was no correlation between capillary RBC velocity and lineal density. A passive inverse relationship between module length and haemodynamics was remarkably absent, providing direct evidence for microvascular flow regulation at the level of the CM. In summary, the CF is an updated paradigm for characterizing RBC distribution in skeletal muscle, and strengthens the theory of capillary networks as major contributors to the signal that regulates capillary perfusion.

A two-compartment model of oxygen transport in skeletal muscle using continuously distributed capillaries.

For future application to studying regulation of microvascular oxygen delivery, a model is developed for O2 transport within an idealized volume of tissue, that is perfused by a continuous distribution of capillaries. Considering oxygen diffusion, convection, and consumption, an O2-dependent transfer term between the capillaries and tissue is used to extend previous single-compartment approaches to include separate tissue and capillary compartments. The coupled tissue-capillary PDE system is considered for unidirectional capillary flow in z, as a simplified model of O2 transport in skeletal muscle, and steady-state 2D solutions are obtained using boundary conditions in x that are consistent with two experimental situations of interest. To validate the continuous capillary model, comparisons are made of an exact nonlinear solution (for no flux at x=0) to results of an established discrete capillary model (solved via finite differences) for varying capillary density, O2 consumption rate, and red blood cell velocity. In addition, comparisons of an approximate linearized solution (for fixed PO2 at x=0) are made to the corresponding discrete capillary solution. Results of the continuous capillary model are presented for varying inlet O2 saturation, showing the utility of the new model for studying physiological problems. Numerical solution of the new model for problems with time dependence and complex geometry is expected to be substantially more efficient than for the corresponding discrete capillary problems.