Regulation of Local Cerebral Blood Flow by Capillary Pericytes: Insights from a Mathematical Model

Introduction: : The human brain relies on a complex microcirculatory network to deliver oxygen and nutrients to neuronal tissue, ensuring its proper function. This network consists of parenchymal arterioles, which penetrate deep into the cortex and branch into a dense capillary system. These vessels must adapt dynamically to local metabolic demands and chemomechanical signals. This allows for the tight regulation of local cerebral blood flow (CBF) is in response to changes in blood pressure and neuronal activity. Mural cells, including smooth muscle cells (SMCs) in arterioles and pericytes (PCs) in capillaries, are central to this regulation. SMCs are the main mediators of myogenic autoregulation and their ability to vasoconstrict as transmural pressure increases is well established. PCs are also thought to regulate the diameter of proximal to arterioles capillaries but their contribution to blood flow regulation has not been thoroughly investigated. Dysfunction in mural cells can lead to microvascular instability and impaired tissue perfusion, which are implicated in various disease states. Given the complexity of cerebral microvascular architecture and the limitations of traditional experimental approaches, computational modeling offers a powerful tool to predict mural cell behavior and assess their impact on blood flow regulation in both health and disease.

Materials and

Methods: : We developed an integrated multiscale mathematical model to study mural cell contributions to cerebral blood flow (CBF) regulation. The model describes membrane potential (Vm) and intracellular calcium dynamics in SMCs, endothelial cells (ECs), capillary ECs, and PCs, incorporating ion channels such as non-selective cation (NSC), inward rectifying K+ (Kir), voltage-operated Ca2+ (VOCC) channels, ion pumps, and exchangers (Fig. 1A). A biomechanical model links SMC/PC calcium mobilization to vessel diameter changes (Fig. 1B), with passive (σ_pass) and active stresses (σ_act) approximated by exponential and bell-shaped functions of diameter, respectively. SMC/PC active tone (A_tone) is a sigmoidal function of intracellular calcium ([Ca²⁺]i) (Eq.1).
σ_tot= σ_pass+A_tone σ_act A_tone= ([Ca^(2+) ]_i^(n_tone ))/([Ca^(2+) ]_i^(n_tone )+K_MCa^(n_tone ) )
An increase in pressure (P) activates NSC channels to initiate vasoactive signaling and establish myogenic tone in pressurized vessels. The integrated models of arterial and capillary electrophysiology and biomechanics are utilized in large scale hemodynamic simulations in reconstructed microvascular networks. This allows us to examine how cell level changes can affect blood perfusion at a macroscopic level.

Results, Conclusions, and Discussions:: At the single-cell level, simulations replicated key experimental findings of mural cell responses to mechanical stimulation. In SMCs, increases in intraluminal pressure induced membrane depolarization, calcium influx through VOCCs, and vasoconstriction. Similarly, PCs exhibit pressure-dependent depolarization and calcium mobilization, yielding a very robust myogenic response in agreement with experiments. Both cell types demonstrate biphasic mechanical behavior: initial passive dilation followed by active constriction as pressure increased. The simulation results validate the model’s ability to capture essential features of mural cell electromechanical coupling.
At the vascular network scale, simulations predict flow, pressure and hematocrit distributions in a ~1 mm3 of brain tissue volume. Simulations assume contractile PCs over the first 3 capillary generations and examine hemodynamics in the presence or absence of PC tone and for different inlet pressures. Simulations suggest that myogenic tone in capillary PCs is needed to maintain steady blood perfusion as pressure changes (myogenic autoregulation). Furthermore, PC may play a critical role for providing sufficient blood perfusion across cortical depths. Loss of capillary tone facilitated redistribution of blood flow at the expense of deeper brain regions. Similarly, compromised pericyte contractility at levels seen in disease states (i.e. Small Vessel Disease of the brain) was predicted to lead to perfusion deficits.
A multiscale mathematical model allows to examine microvascular hemodynamics and how they are affect by cell level changes. Simulation results highlight the role of capillary PCs as an important regulatory component for maintaining steady brain perfusion as blood pressure changes and for modulating blood flow distribution across cortical depths and thus protecting blood supply to deeper brain regions.

Acknowledgements and/or References (Optional):: This work is supported by the National Institute of Neurological Disorders and Stroke and the National
Institute of Aging of the NIH under award number R01NS19971.