Integrative Modeling of Functional Hyperemia: From Ion Channel Activity to Functional Imaging

Abstract

Neuronal activity signals local changes in functional hyperemia which match metabolic demands for oxygen (O2) -and other nutrients, referred to as Neurovascular Coupling (NVC). NVC is essential for proper functioning of the brain and is impaired in various clinical conditions including Alzheimer's disease, stroke and aging (Phillips, et al., JCBFM, 2016). The emerging paradigm is that neurons and astrocytes release vasoactive mediators in the perivascular space of penetrating arterioles to increase their diameter and blood supply. Recent evidence supports the concept that brain capillaries can also act as a neuronal activity-sensing network, and initiate electrical signal that propagate upstream to cause dilation and increase local blood flow (Longden, et al., Nature, 2017). How signaling of neuronal activity to the capillaries intersects with arteriole-level communication is completely unknown. In this study, we propose an integrative modeling approach to model microcirculatory responses to NVC mediators and their effect on the regulation of blood flow, tissue perfusion, and oxygenation. Single cell models of endothelial cells (EC) and smooth muscle cells (SMC) describe membrane electrophysiology and Ca2+ dynamics. Cells are coupled through gap junctions to form branched capillary networks connected to parenchymal arterioles to examine capillary to arteriole communication. Hemodynamic responses are governed by conservation of flow, Fåhræus–Lindqvist effect, and the phase separation effect (Pries, Secomb, AJPHAP, 2005). Oxygen simulations provide PO2 within vessels and in the tissue. Simulations are extended to a macroscale level by incorporating reconstructed brain vascular networks from (Blinder, et al., Nature, 2013). The model predicts changes in tissue perfusion and oxygen distribution in response to neuronal activity. The model accounts for dynamic regulation of PA diameters by NVC mediators and propagating electrical signals from connected capillary beds. Simulations suggest an important role of capillary-level NVC in regulating functional hyperemia. The theoretical framework presented allows for testing proposed NVC mechanisms and assisting in the interpretation of macroscale functional imaging responses in health and in disease. Support or Funding Information This work was supported by NIH grant 1R15HL121778-01A1 A, B) Cell models for capillary EC, parenchymal arteriole EC and SMC simulate electrophysiology and Ca2+ dynamics in response to mechanical stimuli or NVC mediators. C) Multicellular models of a Capillary and a PA are constructed. D) Capillaries are coupled to a PA to form a local vascular network and detailed simulations of blood flow and O2 distribution are performed. E) Predicted changes in Oxy/Deoxy Hb distribution are translated to responses in functional imaging scans such as BOLD fMRI. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.