A mathematical model for persistent post-CSD vasoconstriction.

Autor: Xu, Shixin, Chang, Joshua C., Chow, Carson C., Brennan, Kevin C., Huang, Huaxiong
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Zdroj: PLoS Computational Biology; 7/15/2020, Vol. 16 Issue 7, p1-24, 24p, 1 Color Photograph, 5 Charts, 6 Graphs
Abstrakt: Cortical spreading depression (CSD) is the propagation of a relatively slow wave in cortical brain tissue that is linked to a number of pathological conditions such as stroke and migraine. Most of the existing literature investigates the dynamics of short term phenomena such as the depolarization and repolarization of membrane potentials or large ion shifts. Here, we focus on the clinically-relevant hour-long state of neurovascular malfunction in the wake of CSDs. This dysfunctional state involves widespread vasoconstriction and a general disruption of neurovascular coupling. We demonstrate, using a mathematical model, that dissolution of calcium that has aggregated within the mitochondria of vascular smooth muscle cells can drive an hour-long disruption. We model the rate of calcium clearance as well as the dynamical implications on overall blood flow. Based on reaction stoichiometry, we quantify a possible impact of calcium phosphate dissolution on the maintenance of F0F1-ATP synthase activity. Author summary: This manuscript links calcium phosphate cluster dissolution in mitochondria to oscillations in vascular smooth muscle cells in putting forward an explanation for deranged vascular dynamics following cortical spreading depression (CSD). CSD is an extraordinary phenomenon in the brain triggered in many adverse events such as migraine with aura, stroke, and traumatic brain injury. As a propagating wave phenomenon, researchers have concentrated on CSD's acute spreading phase. However, CSD exhibits stereotyped post-acute dynamics, and is a candidate for explaining longer-lasting derangement in brain activity. Our explanation for the post-acute dynamics relates to superphysiological calcium buffering in vascular smooth muscle cells. In CSD, extracellular calcium floods into cells in the brain, including neurons, vascular cells, and glial cells. When cells are at extremely high calcium loads, mitochondria buffer excess calcium by forming calcium phosphate precipitate species. The existence of these species stabilizes the free ionic calcium concentration within mitochondria to a set point determined by thermodynamic equilibrium of the solvation process. This concentration is elevated relative to normal mitochondria concentration—we explore the implications of the stable elevation on calcium dynamics within vascular smooth muscle cells and relate these dynamics to macroscopic physiological behavior of the vasculature after CSD. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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