(B-55) Investigating Functional Hyperemia in Mouse Brain: A Systems Biology Perspective

Introduction:: This study utilizes systems biology approaches to explore the complexities of Neurovascular Coupling (NVC), focusing on its autoregulatory mechanism (myogenic tone) and functional hyperemia (FH), the two primary mechanisms of the NVC system in the somatosensory cortex of awake mouse brains. Our findings propose a model for the interplay between Smooth Muscle Cells (SMCs) of Penetrating Arterioles (PAs) and surrounding cells, including endothelial cells (ECs) and astrocyte endfeet. Furthermore, we highlight the importance of myogenic tone development in maintaining the stability of the NVC system in response to induced neural activities.

Materials and Methods:: We developed mathematical frameworks encompassing hemodynamic analysis and computational models for SMCs and ECs to study NVC. Initially, we designed and implemented an artificial microvascular network of the mouse brain, consisting of interconnected nodes and segments. Each segment is modeled as a cylindrical tube with length and diameter determining the resistance to blood flow. We used recently published data to establish the characteristics of various compartments within the network and performed a comprehensive statistical analysis of two-photon-imaged murine cerebral vasculature to better understand the structure and topology of brain vasculature. These data were incorporated into the artificial vasculature design, which we validated for similarity to real mouse brain vasculature and functionality for subsequent analysis. Subsequently, we carried out an in silico analysis of SMCs, incorporating embedded myogenic tone, to create a computational model grounded in the most recent biological findings. We examined the signaling pathways from ECs to SMCs and integrated them into the SMC computational model. This model was then implemented into the PA segments of the custom-designed artificial vasculature, allowing us to analyze NVC and investigate hypotheses that were previously inaccessible without employing computational analysis.

Results, Conclusions, and Discussions:: We employed systems biology to address unanswered questions in the NVC research field. Our primary findings, as depicted in the figure, revealed the fundamental feedforward and feedback mechanisms contributing to FH in PA SMCs, which play a crucial role in the NVC system. We showed that arteriolar ECs convey regulatory signals, either chemical or electrical, to PA SMCs through feedforward pathways, leading to PA vasodilation. Furthermore, we demonstrated that SMCs develop a feedback pathway controlling the degree of muscle relaxation and creating a more stable system in brain vasculature. This feedback mechanism detects intravascular pressure (IP) in vessel segments and triggers vasoconstriction if feedforward mechanisms induce excessive dilation. We also emphasized the contribution of astrocyte endfeet-derived factors in the NVC system, specifically in PA SMCs, impacting long-term FH.

In addition to our primary objective, we gained insights into the role of different vasculature zones in blood supply to capillaries. Our hemodynamic analyses determined that the majority of the pressure drop occurs along PAs and sphincters in upper layers, and PAs in deeper layers. We found that vascular segments with high levels of α-SMA content, including SMCs at PAs and sphincters, and ensheathing pericytes at the transitional zone, play a significant role in ensuring proper blood perfusion. These segments, as primary regulators of IP at initial nodes of the capillary network, exert a substantial influence on blood flow in the brain. We also demonstrated that biphasic vascular reactivity is a signature of myogenic-tone based negative feedback and highlighted the importance of myogenic tone development in all mural cells, including pericytes.

In conclusion, FH could serve as a diagnostic tool for detecting diseases with NVC dysfunction. A deeper understanding of vascular hemodynamic signals during FH is essential for researchers investigating NVC dysfunctionality in disease models. By examining vascular diameter change and decoding the underlying vasodilatory pathways using computational analysis, this study contributes to characterizing dominant pathways in FH, which may pave the way for experiments that uncover dysfunctional pathways detectable through simple imaging techniques in more accessible tissues, such as the retina, due to its similarities to the brain's vascular system.

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