Spatial and temporal patterns of nitric oxide diffusion and degradation drive emergent cerebrovascular dynamics

Abstract

Nitric oxide (NO) is a gaseous signaling molecule that plays an important role in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle surrounding cerebral arterioles, driving vasodilation. However, the rate of NO degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how this might impact NO signaling dynamics is not completely understood. We used simulations to investigate how the spatial and temporal patterns of NO generation and degradation impacted dilation of a penetrating arteriole in cortex. We found that the spatial location of NO production and the size of the vessel both played an important role in determining its responsiveness to NO. The much higher rate of NO degradation and scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. Large vasodilation events could be followed by post-stimulus constrictions driven by the increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations could also be generated. We found that these dynamics could be enhanced by elevation of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle cell anemia, or following blood transfusions. Finally, we show that changes in blood flow during hypoxia or hyperoxia could be explained by altered NO degradation in the parenchyma. Our simulations suggest that many common vascular dynamics may be emergent phenomena generated by NO degradation by the blood or parenchyma.

Inflammation, Nitro-Oxidative Stress, Impaired Autophagy, and Insulin Resistance as a Mechanistic Convergence Between Arterial Stiffness and Alzheimer’s Disease

“…It has been proposed that downregulation of cerebrovascular eNOS expression predisposes certain brain areas to lose their BBB integrity ( Soares et al, 2015 ; Al-Zaiti et al, 2018 ; Munji et al, 2019 ; Zhang et al, 2019 ; Bernstein et al, 2020 ). Intact endothelium and consequent preserved NO production in the cerebrovasculature is thus important to prevent stroke, cerebrovascular disease and neurodegeneration ( Tabatabaei and Girouard, 2014 ; Khan et al, 2019 ; Haselden et al, 2020 ). A study from a metabolic point of view concluded that Type 1 diabetes driven eNOS-deficiency increases BBB permeability ( Mayhan et al, 2015 ).…”

Iliski, a software for robust calculation of transfer functions

“…This coupling between neural activity and hemodynamics is known as neurovascular coupling (NVC) [12]. While there are many successful phenomenological models of NVC [3,[13][14][15][16][17], most physiology-based models of neurovascular coupling [18][19][20][21] focus on a single cellular mechanism. As NVC is mediated through multiple processes (several molecular cascades, each mediated by different cell types), a more integrated approach is necessary.…”

Nitrergic neurons of the forepaw representation in the rat somatosensory and motor cortices: A quantitative study

“…As shown for excitatory pyramidal neurons, geometric characteristics of an identified neuronal subpopulation are likely to differ across functionally distinct cortical areas, reflecting local properties of vertical and horizontal processing flows (Elston, 2002; Elston et al, 2006). Since NO release may affect local neurovascular dynamics (Haselden et al, 2020) in a spatially restricted zone around the dendritic field, comparing the cortical distribution and the fine morphological arrangement of dendritic arbors of NNs across distinct cortical processing fields or compartments should contribute to a better understanding of how inhibitory NNs relate to local processing circuits.…”