Nitrite-Mediated Hypoxic Vasodilation Predicted from Mathematical Modeling and Quantified from in Vivo Studies in Rat Mesentery

Buerk, Donald G.; Liu, Yien; Zaccheo, Kelly A.; Barbee, Kenneth A.; Jaron, Dov

doi:10.3389/fphys.2017.01053

Cited by 4 publications

(5 citation statements)

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“…Computational models of diffusion have complemented experimental techniques to give us insights into how NO signals to the vasculature. Pioneering work by Lancaster [ 39 ], Wood and Garthwaite [ 40 ], and others [ 60 , 80 , 96 , 101 , 102 , 104 , 105 , 201 , 227 ] have demonstrated the importance of NO degradation by the blood in shaping the efficacy of NO signaling. Building upon their work, we apply the insights gained from modeling NO dynamics to neurovascular coupling.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the lack of an known oxygen sensor in the brain, hypoxia will dilate and hyperoxia will constrict cerebral arterioles [180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197]. These cerebrovascular responses to blood oxygenation are modulated by NO availability [180,192,[198][199][200][201][202], occur under isocapnic conditions [200,202] and constant pH [200]. We wanted to investigate if changes in NO consumption due to oxidative reactions in the parenchyma could contribute to hypoxia-induced vasodilation.…”

Section: No Can Act As Sensor Of Cerebral Oxygenationmentioning

confidence: 99%

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

2020

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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.

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Section: Discussionmentioning

confidence: 99%

Section: No Can Act As Sensor Of Cerebral Oxygenationmentioning

confidence: 99%

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

2020

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“…Computational models of diffusion have complemented experimental techniques to give us insights into how NO signals the vasculature. Pioneering work by Lancaster 38 , Wood and Garthwaite 39 , and others 59, 76, 91, 96, 97, 99, 100, 178, 183 have demonstrated the importance of NO degradation by the blood in shaping the efficacy of NO signaling. Building upon their work, we apply the insights gained from modeling NO dynamics to neurovascular coupling.…”

Section: Discussionmentioning

confidence: 99%

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

Haselden

Kedarasetti

Drew

2019

Preprint

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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...

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“…To evaluate the potential physiological role of XOR and AO in the generation of NO, different models have been explored, such as models of ischemia/reperfusion and hypoxic injury in heart [38] , [39] , [45] , liver [39] , [40] , [185] , kidney [186] , [187] , [188] , blood vessels and cells (models of inflammation) [189] , [190] , [191] , [192] , [193] , [194] , [195] , pulmonary hypertension [55] , [65] , [196] , [197] , and several other, that include the "less physiological" homogenates (of heart, aorta, liver, lung, kidney) ( Fig. 9 ) [38] , [55] , [65] , [164] , [165] , [186] , [190] , but also animal models [38] , [45] , [65] .…”

Section: Xor and Ao-catalyzed Nitrite Reduction: Models To Envisage Tmentioning

confidence: 99%

Putting xanthine oxidoreductase and aldehyde oxidase on the NO metabolism map: Nitrite reduction by molybdoenzymes

Maia

Moura

2018

Redox Biology

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Nitric oxide radical (NO) is a signaling molecule involved in several physiological and pathological processes and a new nitrate-nitrite-NO pathway has emerged as a physiological alternative to the "classic" pathway of NO formation from L-arginine. Since the late 1990s, it has become clear that nitrite can be reduced back to NO under hypoxic/anoxic conditions and exert a significant cytoprotective action in vivo under challenging conditions. To reduce nitrite to NO, mammalian cells can use different metalloproteins that are present in cells to perform other functions, including several heme proteins and molybdoenzymes, comprising what we denominated as the "non-dedicated nitrite reductases". Herein, we will review the current knowledge on two of those "non-dedicated nitrite reductases", the molybdoenzymes xanthine oxidoreductase and aldehyde oxidase, discussing the in vitro and in vivo studies to provide the current picture of the role of these enzymes on the NO metabolism in humans.

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Nitrite-Mediated Hypoxic Vasodilation Predicted from Mathematical Modeling and Quantified from in Vivo Studies in Rat Mesentery

Cited by 4 publications

References 74 publications

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

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

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

Putting xanthine oxidoreductase and aldehyde oxidase on the NO metabolism map: Nitrite reduction by molybdoenzymes

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