The endothelial glycocalyx promotes homogenous blood flow distribution within the microvasculature

Abstract

Many common diseases involve impaired tissue perfusion, and heterogeneous distribution of blood flow in the microvasculature contributes to this pathology. The physiological mechanisms regulating homogeneity/heterogeneity of microvascular perfusion are presently unknown. Using established empirical formulations for blood viscosity modeling in vivo (blood vessels) and in vitro (glass tubes), we showed that the in vivo formulation predicts more homogenous perfusion of microvascular networks at the arteriolar and capillary levels. Next, we showed that the more homogeneous blood flow under simulated in vivo conditions can be explained by changes in red blood cell interactions with the vessel wall. Finally, we demonstrated that the presence of a space-filling, semipermeable layer (such as the endothelial glycocalyx) at the vessel wall can account for the changes of red blood cell interactions with the vessel wall that promote homogenous microvascular perfusion. Collectively, our results indicate that the mechanical properties of the endothelial glycocalyx promote homogeneous microvascular perfusion. Preservation or restoration of normal glycocalyx properties may be a viable strategy for improving tissue perfusion in a variety of diseases.

Keywords: glycocalyx; microvascular perfusion; oxygen delivery; perfusion heterogeneity.

Fig. 1.

Schema of established determinants of microvascular blood flow distribution based on the literature. A: relationships between parameters influencing microvascular blood flow distribution during the transition from multifile to single file flow (left) and during red blood cell (RBC) deformation (right). Causal increases (i.e., increases in A cause increases in B) are indicated by solid arrows, whereas causal decreases are indicated by dashed arrows. Here, D is vessel diameter, Q is flow rate, H is hematocrit, and μ is viscosity. B: blood viscosity (y-axis) changes with changing vessel diameter (x-axis) both in vivo and in vitro. In vitro, increasing vessel diameter increases microvascular blood viscosity at all physiologically relevant vessel diameters. In vivo, increasing vessel diameter decreases blood viscosity at the capillary and precapillary levels but otherwise increases blood viscosity. C: ratio of daughter vessel hematocrit to parent vessel hematocrit (y-axis) as a function of the fraction of the parent vessel flow rate received by the daughter vessel (x-axis). An idealized bifurcation in which all vessels are 10 μm in diameter and feed hematocrit of 0.45 was simulated to create this graph. D: derivative of microvascular blood viscosity (y-axis) with respect to vessel hematocrit (x-axis). Although increases in hematocrit increase blood viscosity both in vivo and in vitro, this effect is much stronger in vivo (41, 45).

Fig. 2.

Parameters used to create idealized arteriolar trees. Each parent vessel terminates at a bifurcation of two smaller vessels. At each bifurcation, the parent vessel is denoted by subscript 0, the smaller daughter vessel is denoted by subscript 1, and the larger daughter vessel is denoted by subscript 2. Bifurcation asymmetry parameter α is defined in terms of the relative diameters of the daughter vessels. The length-to-diameter ratio is held constant across vessel generations. Murray's cube law (33) was used to define the scaling of successive vessel generations. Here, D is vessel diameter, L is vessel length, and the subscripts denote the vessel segments.

Fig. 3.

Influences of microvascular blood viscosity on microvascular perfusion heterogeneity in a simulated arteriolar tree. A: schematic of the idealized arteriolar networks obtained by varying the bifurcation parameter α (see Fig. 1). All arteriolar networks simulated consisted of seven successive vessel generations with fractal vessel architecture. B: heterogeneity (SD/mean) of the whole network transit time is reduced in vivo (blood vessels) compared with in vitro (glass tubes) for all values of α. C: heterogeneity (SD/mean) of the terminal vessel transit time is reduced in vivo compared with in vitro for all values of α. D: SD of the fractional daughter vessel flow rate is subtly increased in vivo compared with in vitro for all values of α. E: SD of the terminal vessel hematocrit is subtly increased in vivo compared with in vitro for all values of α.

Fig. 4.

Influences of microvascular blood viscosity on blood flow distribution at an idealized capillary bifurcation. A: schematic of idealized capillary bifurcation. Arrows indicate the direction of flow. Both daughter vessels and the parent vessel are all of identical diameter. Daughter vessels differ only in their resistance to flow distal to the bifurcation (ρ₁ and ρ₂). B: fraction of parent vessel flow rate received by daughter vessel 1 as a function of relative downstream resistance (ρ₁/ρ₂). In vivo blood viscosity behaviors provide a more equal distribution of flow for all values of ρ₁/ρ₂. C: fraction of parent vessel hematocrit in daughter vessel 1 as a function of relative downstream resistance (ρ₁/ρ₂). In vivo blood viscosity behaviors result in less downstream capillary hematocrit heterogeneity for all values of ρ₁/ρ₂.

Fig. 5.

Effects of glycocalyx properties on the determinants of blood viscosity. A: representative velocity profiles within the vessel with and without a RBC in the lumen. Shaded gray areas represent the glycocalyx. Compare with the results of Secomb et al. (50). B: sensitivity of microvascular blood viscosity to hematocrit decreases with increasing glycocalyx permeability (Darcy permeability). This effect is influenced little by glycocalyx width. C: effective blood viscosity at the capillary level increases with decreasing glycocalyx permeability. This effect is further compounded by the effects of glycocalyx width.

Fig. 6.

Summary of findings. Our simulations concern the distribution of blood flow and RBCs within precapillary arterioles and capillaries. At this level of the circulation, total flow rate has already been determined by upstream arteries. At the arteriolar level (see Flow distribution in branching arteriolar networks and Fig. 3), both diameter and hematocrit dependencies of blood viscosity influence flow distribution. At the capillary level (see Flow distribution at an idealized capillary bifurction and Fig. 4), the hematocrit dependency of blood viscosity modulates flow distribution. Based on the influences of glycocalyx properties on the diameter and hematocrit dependencies of blood viscosity (see Influences of glycocalyx properties on the determinants of blood viscosity and Fig. 5), this suggests that both glycocalyx width and permeability modulate flow distribution at the arteriolar level, whereas glycocalyx permeability is the primary determinant at the capillary level.