Red blood cells stabilize flow in brain microvascular networks

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.

毛细血管是所有组织开展氧气与营养物质交换的核心位点。尽管其发挥着不可或缺的生理功能，但目前学界对皮层毛细血管床的灌注与血流调控机制的认知仍较为有限。本研究借助活体实验测量与解剖学精准微血管网络血流模拟，探究红细胞（red blood cells, RBCs）对微血管血流的影响。基于上述活体与计算机模拟实验，本研究发现RBCs的作用会使毛细血管分叉处的流出流速趋于均等，我们将这一现象命名为"均衡分叉（well-balanced bifurcations）"。本研究的模拟结果进一步揭示，血细胞比容异质性直接由RBC动力学行为导致，具体体现为RBC在分叉处的不均等分配及其对血管阻力的影响。上述结果首次为RBC动力学行为对皮层微血管血流场的影响提供了活体实验证据。通过对血流模拟结果的结构与功能分析，本研究发现毛细血管直径的局部变化会改变局部血流与RBC分布。在长度为100 μm的血管段上发生10%的管径扩张后，位于均衡分叉下游的扩张血管内的平均流量提升21%，血管内的RBC数量平均增加27%。值得注意的是，上游分叉处的流出流速越均衡，RBC数量的上调效果越显著。综上，本研究认为毛细血管水平的管径变化具备局部改变血流场与RBC分布的潜力。此外，本研究结果表明，流出流速的均衡化有助于提升灌注的稳定性。基于计算机模拟结果，本研究推测血液的双相特性与微观尺度调控，对于实现精准适配的氧气与能量底物供应至关重要。