A model of neurovascular coupling : the neurovascular unit and the effect of the endothelial cells’ mitochondria-associated endoplasmic reticulum membranes
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Date
2024-07-11
Authors
Κυριακού, Θεοδώρα
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Abstract
The neurovascular unit consists of neurons (NEs), astrocytes (ACs), vasculature (endothelial cells (ECs) and mural cells), the vasomotor apparatus (smooth muscle cells (SMCs) and pericytes) and mi-croglia. Together, these function in the homeostatic haeomodynamic response of cerebral hyperae-mia, a central nervous system homeostatic mechanism that increases blood supply to neural tissue when necessary. A better understanding of functional hyperaemia is important not only for the field of neuroscience but for the medical one as well, as neuroimaging techniques, such as fMRI, fNRIS and PET scans monitor cerebral blood flow and can, subsequently, measure and locate brain activity. More specifically, an fMRI detects the blood-oxygen-level-dependent (BOLD) signal which reflects changes in deoxyhemoglobin triggered by alterations in brain blood flow and blood oxygenation. fNIRS is a non-invasive, portable method employing near-infrared light propagating diffusely through the scalp and brain, for functional monitoring and imaging of human brain hemodynamics, while a PET scan uses injected radioactive material to visualise active areas of the brain.
This thesis reports the development of a lumped-element model of a neurovascular unit (NVU). The cells involved in this model are a neuron, an astrocyte, an endothelial cell and a smooth muscle cell. The pathways that affect the radius of a blood capillary in the brain after the creation of a neural pulse were investigated. These are the potassium pathway, the astrocytic calcium pathway in combi-nation with a transient receptor potential cation channel in the astrocytic endfoot and the nitric oxide pathway. A computational model was built that includes the three pathways, which can be turned on and off with suitable switches. We first analysed the model's results when it contains solely the po-tassium pathway. The same procedure was followed for the astrocytic calcium pathway with the TRPV4 channel and the nitric oxide pathway.
The results of the above were compared with each other but also with the model which includes all the pathways mentioned. To compare the results, diagrams were created for various system vari-ables. The graph depicting the radius of the vessel over time was the most important among them. We presented the response of the vessel’s radius to the neural pulse for each pathway alone and for all three together. What emerged from this analysis were the following:
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The potassium pathway is responsible for the rapid response of the vessel to neuronal activity.
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The nitric oxide pathway is responsible for the longer dilation of the blood vessel after the onset of the pulse.
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The astrocytic calcium pathway strengthens, to a small extent, the dilation of the blood vessel.
Also, the mathematical model by Moshkforoush et al. was incorporated. This one focuses on the inositol triphosphate (IP3)-induced Ca2+ mobilisation in the endothelial cell that accounts for all major subcellular Ca2+ compartments (i.e., cyt, ER, Mt), their respective Ca2+ channels and buffering, and considers explicitly the ER-Mt Ca2+ microdomains as a distinct Ca2+ pool (μd). Mitochondria can up-take and store significant amounts of Ca2+. Their buffering potential allows them to modulate Ca2+ mobilisation in the cytosol including oscillatory dynamics. It was postulated that the presence of the ER-Mt μd may shape the [Ca2+]cyt oscillatory dynamics. A mathematical model by Penny et al. previ-ously explored the role of the ER-lysosome μd in driving [Ca2+]cyt dynamics in stimulated fibroblasts by varying the distribution of two-pore Ca2+ channels on lysosomes. They showed that the distribution and density of the Ca2+ channels on lysosomes that face the ER-lysosome μd regulate the IP3R-de-pendent [Ca2+]cyt oscillations.
A mathematical study that has explored the role of the ER-Mt μd prior to the one by Moshkforoush et al. is the model by Qi et al., where Ca2+ diffusion from a point source, a cluster of IP3Rs to the MCU, was assumed and the distance between the ER and Mt compartments was varied (MCU activity de-pended on the local [Ca2+], while JIP3R (J represents flux) was only a function of [Ca2+]cyt).
In contrast, in the Moshkforoush et al. model, an explicit μd compartment with a variable volume which depended on the ER-Mt distance was incorporated. This approach allowed the separation of IP3Rs, as well as MCU, SERCA, and mNCX channels, into two distinct pools; one pool of IP3Rs facing the μd and, thus, their activity depends on [Ca2+]μd, and another pool of IP3Rs facing the cytosol and are exposed to [Ca2+]cyt. This resulted in identifying conditions where the μd and the Mt play a regu-latory role, aside from their modulatory role, in [Ca2+] oscillatory dynamics. More specifically, the incorporation of the μd and the channel connectivity coefficients for the above four channels led to the emergence of two distinct oscillatory regions at low and intermediate [IP3].
In the thesis, the focus was on the oscillatory regions at low [IP3], where the series of events that result in initiation and maintenance of [Ca2+]cyt oscillations is as follows:
The [IP3] causes an increased efflux from cyt-facing IP3Rs, which brings the [Ca2+]cyt to sufficient levels for the initiation of Ca2+ bursting. High [Ca2+]μd, on the other hand, inactivates the μd-facing IP3Rs at high levels of stimulation. Thus, in this region, periodic opening of cyt-facing IP3Rs governs the oscillations of [Ca+2]cyt. Overall, the incorporation of the microdomains led to oscillations in the graphs of various molecules included in the model.
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Keywords
Neurovascular coupling, Fortran 90, Anatomy, Nervous system, Cerebral blood flow