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 1 in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle 2 surrounding cerebral arterioles, driving vasodilation.However, the rate of NO 3 degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how 4 this might impact NO signaling dynamics is not completely understood. We used 5 simulations to investigate how the spatial and temporal patterns of NO generation and 6 degradation impacted dilation of a penetrating arteriole in cortex. We found that the 7 spatial location of NO production and the size of the vessel both played an important role 8 in determining its responsiveness to NO. The much higher rate of NO degradation and 9 scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. 10Large vasodilation events could be followed by post-stimulus constrictions driven by the 11 increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations 12 could also be generated. We found that these dynamics could be enhanced by elevation 13 of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle 14 cell anemia, or following blood transfusions. Finally, we show that changes in blood flow 15 during hypoxia or hyperoxia could be explained by altered NO degradation in the 16 parenchyma. Our simulations suggest that many common vascular dynamics may be 17 emergent phenomenon generated by NO degradation by the blood or parenchyma. 18 19 20 21 22 23 fold faster than the surrounding tissue 73,75-78 . Because NO reacts with hemoglobin at 70 much higher rates than the tissue, the hemoglobin present inside a vessel plays an 71 appreciable role in shaping NO concentrations at the smooth muscle where it acts. Under 72 normal conditions, most hemoglobin in the blood in confined to red blood cells, with low 73 levels in the plasma. Due to fluid dynamics 79-81 , red blood cells will be excluded from the 74 few micrometer-thick cell free layer next to the endothelial cells, providing a measure of 75 spatial separation between the region of high NO degradation and the smooth muscles. 76However, if hemoglobin levels in the plasma rise (due to pathology or other processes) 82-77 89 , this will greatly increase the degradation rate of NO in the plasma, leading to decreased 78 NO levels in the smooth muscle 83,[90][91][92] . NO's diffusive properties and known reaction 79 rates lend themselves to computational approaches to understanding NO 80 signaling 38,59,75,78,[93][94][95][96][97][98] . While there have been detailed and informative models of NO 81 signaling from endothelial cells 59,91,96,99,100 showing that the size of the arteriole 75 and 82properties of the blood 96 are vital components to understanding NO signaling, the insight 83 from these models that the spatial location of blood plays an important role in the 84 degradation of NO has not been applied to neurovascular coupling or in a dynamic setting. 85 Intriguingly, in...

nNOS-expressing interneurons control basal and behaviorally evoked arterial dilation in somatosensory cortex of mice

“…Another possibility could be the spatial location of the generation of the vasodilator(s) relative to the arterioles, particularly in the case of nitric oxide. Simulation of NO diffusion and degradation dynamics in the tissue have shown that NO production needs to be very close (of order microns to tens of microns) to the arteriole in order to exert an appreciable dilatory effect ( Haselden et al, 2020 ). It could be that NO is produced closer to pial vessel (potentially in the processes of more superficial type two neurons), than near the penetrating arterioles in the superficial layers.…”

“…In vitro studies have shown that activation of Substance P receptors drives large increases in activity ( Endo et al, 2016 ; Williams et al, 2019 ; Williams et al, 2018 ), potentially accounting for the asymmetry of vascular responses to the application of blockers and activators of these receptors. Simulations have shown that the location of NO production relative to the arteriole has a large impact on its efficacy ( Haselden et al, 2020 ), so the location of the infected neurons relative to the arterioles may cause some variability. We performed our experiments in awake mice, as anesthetics cause large decreases in brain metabolism, cardiovascular output, and ongoing neural activity ( Gao et al, 2017 ), but there could be some variability associated with the mice being awake.…”

A validated reduced-order dynamic model of nitric oxide regulation in coronary arteries

“…Their results showed the possibility of using the fractional flow-mediated dilatation (FFMD) parameter to differentiate the endothelial function between young and middle age groups. Also, in another study, Haselden et al [34] showed that both the spatial location of NO production and the size of the vessel play an important role in determining its response to NO. They also showed that changes in blood flow during hypoxia or hyperoxia could indicate a decrease in NO in the parenchyma.…”

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 mechanism. As NVC is mediated through multiple processes, a more integrated approach is necessary.…”