Red blood cells stabilize flow in brain microvascular networks

Abstract

Capillaries are the prime location for oxygen and nutrient exchange in all tissues. Despite their fundamental role, our knowledge of perfusion and flow regulation in cortical capillary beds is still limited. Here, we use in vivo measurements and blood flow simulations in anatomically accurate microvascular network to investigate the impact of red blood cells (RBCs) on microvascular flow. Based on these in vivo and in silico experiments, we show that the impact of RBCs leads to a bias toward equating the values of the outflow velocities at divergent capillary bifurcations, for which we coin the term “well-balanced bifurcations”. Our simulation results further reveal that hematocrit heterogeneity is directly caused by the RBC dynamics, i.e. by their unequal partitioning at bifurcations and their effect on vessel resistance. These results provide the first in vivo evidence of the impact of RBC dynamics on the flow field in the cortical microvasculature. By structural and functional analyses of our blood flow simulations we show that capillary diameter changes locally alter flow and RBC distribution. A dilation of 10% along a vessel length of 100 μm increases the flow on average by 21% in the dilated vessel downstream a well-balanced bifurcation. The number of RBCs rises on average by 27%. Importantly, RBC up-regulation proves to be more effective the more balanced the outflow velocities at the upstream bifurcation are. Taken together, we conclude that diameter changes at capillary level bear potential to locally change the flow field and the RBC distribution. Moreover, our results suggest that the balancing of outflow velocities contributes to the robustness of perfusion. Based on our in silico results, we anticipate that the bi-phasic nature of blood and small-scale regulations are essential for a well-adjusted oxygen and energy substrate supply.

The severity of microstrokes depends on local vascular topology and baseline perfusion

“…This is in contrast to the occlusion of DAs where the flow rate does not fully recover until the 10 th downstream vessel and where the infarct volume is as large as 220 nl [1,2,28]. Our results agree qualitatively with previous observations where we studied the impact of single capillary dilations of 10% [40]. As this alteration is significantly smaller than the complete occlusion of a capillary, the flow changes in response to dilation are even limited to capillaries directly adjacent to the dilated vessel.…”

“…It is also important to note that by looking at the smallest possible scale of occlusion valuable insights on the robustness of perfusion can be gained and our knowledge of topological characteristics of cortical capillary beds can be extended. Here, we employ blood flow simulations in realistic microvascular networks from the mouse cortex [28,39,40] to study the impact of single capillary occlusions on the perfusion of the cortical microvasculature. Using an in silico approach comes with several advantages.…”

“…First of all, it is challenging to monitor blood flow changes in vivo with single vessel resolution in multiple vessels or even entire vascular networks simultaneously. This problem is even more pronounced, if the focus is on blood flow changes in the capillary bed, which is highly interconnected [26,28,39,[41][42][43] and in which the flow field is highly heterogeneous and fluctuating [39,40,[44][45][46][47]. For a given numerical modeling setup the flow field is known in every vessel at any given moment.…”

Local vs. Global Blood Flow Modulation in Artificial Microvascular Networks: Effects on Red Blood Cell Distribution and Partitioning

“…To understand regulation mechanisms during functional activation it is essential to study the fluid dynamics in capillary networks and take into account the RBC dynamics and partitioning at the level of microvascular bifurcations. The heterogeneity in the local blood flow distribution is a direct consequence of the non-uniform RBC separation between daughter branches of diverging bifurcations (Schmid et al, 2019 ). At diverging bifurcations the outflow branch with a higher flow rate usually receives a disproportionally higher RBC fraction [phenomenon known as Zweifach-Fung effect (Fung, 1973 ; Doyeux et al, 2011 )].…”

“…Reverse partitioning was found to be more likely for high perfusion pressures (Clavica et al, 2016 ; Mantegazza et al, 2020 ), skewed hematocrit profiles in the parent vessels of diverging bifurcations (Balogh and Bagchi, 2018 ; Mantegazza et al, 2020 ) or in case of autoregulation mechanisms due to cell-cell interactions (Balogh and Bagchi, 2018 ). These very local phenomena have a direct impact on the larger scale of microvascular networks leading to heterogenous RBC distribution and altered flow and pressure fields (Schmid et al, 2019 ).…”