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

2019 ◽  
Author(s):  
William Haselden ◽  
Ravi Teja Kedarasetti ◽  
Patrick J. Drew
Keyword(s):  
Nitric Oxide ◽  
Temporal Patterns ◽  
Spatial Location ◽  
No Production ◽  
Spatial And Temporal Patterns ◽  
Signaling Dynamics ◽  
Blood Relative ◽  
No Signaling ◽  
Cerebral Arterioles ◽  
Nitric Oxide Diffusion

AbstractNitric 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 phenomenon generated by NO degradation by the blood or parenchyma.

Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling

2007 ◽  
Vol 292 (4) ◽  
pp. H1995-H2003 ◽  
Author(s):  
Zuo-Hui Shao ◽  
Wei-Tien Chang ◽  
Kim Chai Chan ◽  
Kim R. Wojcik ◽  
Chin-Wang Hsu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Therapeutic Hypothermia ◽  
Optimal Timing ◽  
No Production ◽  
Early Reperfusion ◽  
No Signaling ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Pkc Activation

Optimal timing of therapeutic hypothermia for cardiac ischemia is unknown. Our prior work suggests that ischemia with rapid reperfusion (I/R) in cardiomyocytes can be more damaging than prolonged ischemia alone. Also, these cardiomyocytes demonstrate protein kinase C (PKC) activation and nitric oxide (NO) signaling that confer protection against I/R injury. Thus we hypothesized that hypothermia will protect most using extended ischemia and early reperfusion cooling and is mediated via PKC and NO synthase (NOS). Chick cardiomyocytes were exposed to an established model of 1-h ischemia/3-h reperfusion, and the same field of initially contracting cells was monitored for viability and NO generation. Normothermic I/R resulted in 49.7 ± 3.4% cell death. Hypothermia induction to 25°C was most protective (14.3 ± 0.6% death, P < 0.001 vs. I/R control) when instituted during extended ischemia and early reperfusion, compared with induction after reperfusion (22.4 ± 2.9% death). Protection was completely lost if onset of cooling was delayed by 15 min of reperfusion (45.0 ± 8.2% death). Extended ischemia/early reperfusion cooling was associated with increased and sustained NO generation at reperfusion and decreased caspase-3 activation. The NOS inhibitor Nω-nitro-l-arginine methyl ester (200 μM) reversed these changes and abrogated hypothermia protection. In addition, the PKCε inhibitor myr-PKCε v1-2 (5 μM) also reversed NO production and hypothermia protection. In conclusion, therapeutic hypothermia initiated during extended ischemia/early reperfusion optimally protects cardiomyocytes from I/R injury. Such protection appears to be mediated by increased NO generation via activation of protein kinase Cε; nitric oxide synthase.

scholarly journals Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling

2013 ◽  
Vol 210 (7) ◽  
pp. 1433-1445 ◽  
Author(s):  
Nataša Obermajer ◽  
Jeffrey L. Wong ◽  
Robert P. Edwards ◽  
Kong Chen ◽  
Melanie Scott ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
De Novo ◽  
Inflammatory Diseases ◽  
Suppressor Cells ◽  
Guanosine Monophosphate ◽  
No Production ◽  
No Signaling

Nitric oxide (NO) is a ubiquitous mediator of inflammation and immunity, involved in the pathogenesis and control of infectious diseases, autoimmunity, and cancer. We observed that the expression of nitric oxide synthase-2 (NOS2/iNOS) positively correlates with Th17 responses in patients with ovarian cancer (OvCa). Although high concentrations of exogenous NO indiscriminately suppress the proliferation and differentiation of Th1, Th2, and Th17 cells, the physiological NO concentrations produced by patients’ myeloid-derived suppressor cells (MDSCs) support the development of RORγt(Rorc)+IL-23R+IL-17+ Th17 cells. Moreover, the development of Th17 cells from naive-, memory-, or tumor-infiltrating CD4+ T cells, driven by IL-1β/IL-6/IL-23/NO-producing MDSCs or by recombinant cytokines (IL-1β/IL-6/IL-23), is associated with the induction of endogenous NOS2 and NO production, and critically depends on NOS2 activity and the canonical cyclic guanosine monophosphate (cGMP)–cGMP-dependent protein kinase (cGK) pathway of NO signaling within CD4+ T cells. Inhibition of NOS2 or cGMP–cGK signaling abolishes the de novo induction of Th17 cells and selectively suppresses IL-17 production by established Th17 cells isolated from OvCa patients. Our data indicate that, apart from its previously recognized role as an effector mediator of Th17-associated inflammation, NO is also critically required for the induction and stability of human Th17 responses, providing new targets to manipulate Th17 responses in cancer, autoimmunity, and inflammatory diseases.

scholarly journals Hyperoxia disrupts vascular endothelial growth factor-nitric oxide signaling and decreases growth of endothelial colony-forming cells from preterm infants

2009 ◽  
Vol 297 (6) ◽  
pp. L1160-L1169 ◽  
Author(s):  
Hideshi Fujinaga ◽  
Christopher D. Baker ◽  
Sharon L. Ryan ◽  
Neil E. Markham ◽  
Gregory J. Seedorf ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Preterm Infants ◽  
No Production ◽  
Vascular Endothelial ◽  
Enos Expression ◽  
Vascular Growth ◽  
Endothelial Colony Forming Cells ◽  
No Signaling ◽  
Endothelial Growth Factor

Exposure of preterm infants to hyperoxia impairs vascular growth, contributing to the development of bronchopulmonary dysplasia and retinopathy of prematurity. Disruption of vascular endothelial growth factor (VEGF)-nitric oxide (NO) signaling impairs vascular growth. Endothelial progenitor cells (EPCs) may play an important role in vascular growth. Endothelial colony-forming cells (ECFCs), a type of EPC, from human preterm cord blood are more susceptible to hyperoxia-induced growth impairment than term ECFCs. Therefore, we hypothesized that hyperoxia disrupts VEGF-NO signaling and impairs growth in preterm ECFCs and that exogenous VEGF or NO preserves growth in hyperoxia. Growth kinetics of preterm cord blood-derived ECFCs (gestational ages, 27–34 wk) were assessed in room air (RA) and hyperoxia (40–50% oxygen) with or without VEGF, NO, or Nω-nitro-l-arginine. VEGF, VEGF receptor-2 (VEGFR-2), and endothelial NO synthase (eNOS) protein expression and NO production were compared. Compared with RA controls, hyperoxia significantly decreased growth, VEGFR-2 and eNOS expression, and NO production. VEGF treatment restored growth in hyperoxia to values measured in RA controls and significantly increased eNOS expression in hyperoxia. NO treatment also increased growth in hyperoxia. Nω-nitro-l-arginine treatment inhibited VEGF-augmented growth in RA and hyperoxia. We conclude that hyperoxia decreases growth and disrupts VEGF-NO signaling in human preterm ECFCs. VEGF treatment restores growth in hyperoxia by increasing NO production. NO treatment also increases growth during hyperoxia. Exogenous VEGF or NO may protect preterm ECFCs from the adverse effects of hyperoxia and preservation of ECFC function may improve outcomes of preterm infants.

scholarly journals Hydrogen sulfide, an enhancer of vascular nitric oxide signaling: mechanisms and implications

2017 ◽  
Vol 312 (1) ◽  
pp. C3-C15 ◽  
Author(s):  
Csaba Szabo
Keyword(s):  
Nitric Oxide ◽  
Hydrogen Sulfide ◽  
Soluble Guanylate Cyclase ◽  
Specific Activity ◽  
Cardiovascular Effects ◽  
Biologically Active ◽  
Reduced Form ◽  
No Production ◽  
Nitric Oxide Signaling ◽  
No Signaling

Nitric oxide (NO) vascular signaling has long been considered an independent, self-sufficient pathway. However, recent data indicate that the novel gaseous mediator, hydrogen sulfide (H2S), serves as an essential enhancer of vascular NO signaling. The current article overviews the multiple levels at which this enhancement takes place. The first level of interaction relates to the formation of biologically active hybrid S/N species and the H2S-induced stimulation of NO release from its various stable “pools” (e.g., nitrite). The next interactions occur on the level of endothelial calcium mobilization and PI3K/Akt signaling, increasing the specific activity of endothelial NO synthase (eNOS). The next level of interaction occurs on eNOS itself; H2S directly interacts with the enzyme: sulfhydration of critical cysteines stabilizes it in its physiological, dimeric state, thereby optimizing eNOS-derived NO production and minimizing superoxide formation. Yet another level of interaction, further downstream, occurs at the level of soluble guanylate cyclase (sGC): H2S stabilizes sGC in its NO-responsive, physiological, reduced form. Further downstream, H2S inhibits the vascular cGMP phosphodiesterase (PDE5), thereby prolonging the biological half-life of cGMP. Finally, H2S-derived polysulfides directly activate cGMP-dependent protein kinase (PKG). Taken together, H2S emerges an essential endogenous enhancer of vascular NO signaling, contributing to vasorelaxation and angiogenesis. The functional importance of the H2S/NO cooperative interactions is highlighted by the fact that H2S loses many of its beneficial cardiovascular effects when eNOS is inactive.

Abstract 106: Signaling Mechanisms Affecting Nitric Oxide Production in Glomerular Podocytes

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Oleg Palygin ◽  
Daria V Ilatovskaya ◽  
Vladislav Levchenko ◽  
Bradley T Endres ◽  
Aron M Geurts ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Kidney Injury ◽  
No Production ◽  
Ang Ii ◽  
Paracrine Factors ◽  
Low Salt ◽  
Potent Vasodilator ◽  
No Signaling ◽  
Glomerular Ultrafiltration ◽  
Salt Sensitive Hypertension

While Nitric Oxide (NO), a potent vasodilator and vital signaling molecule, has been shown to contribute to the regulation of glomerular ultrafiltration, its role in podocytes during the pathogenesis of salt-sensitive hypertension has not yet been thoroughly examined. Recent studies have demonstrated that the deficiency of eNOS (the enzyme responsible for synthesizing NO) exacerbates renal injury and accelerates development of proteinuria and glomerulosclerosis. Considering this, we hypothesized that the podocytes of hypertensive animals would exhibit reduced NO production in response to various paracrine factors and this directly contributes to proteinuria. To test this, we isolated glomeruli from the kidneys of Dahl salt-sensitive (SS) rats fed either a high salt (HS; 4% NaCl, 3 weeks) or low salt (LS; 0.4% NaCl) diet and loaded podocytes with a combination of NO and Ca 2+ ionophores (DAF-FM and Fura Red, respectively). Changes in fluorescence were observed with the use of confocal microscopy in response to adenosine triphosphate (ATP), angiotensin II (Ang II), and H 2 O 2 . Application of Ang II or H 2 O 2 resulted in activation of both NO and [Ca 2+ ] i ; fluorescent transients which were significantly elevated in the soma and foot processes of podocytes of LS fed rats. In contrast, ATP specifically activated only changes in [Ca 2+ ] i , but did not have any effects on NO production. Ang II treatment also caused hypertrophy of the podocytes, whereas ATP had no effect on cell volume (41.1±7.7 vs. 0.1±3.6% increase for Ang II and ATP, respectively; P <0.05). Collectively, our results show that in contrast to [Ca 2+ ] i , which is modulated by all studied paracrine molecules, NO is produced by podocytes only in response to Ang II and H 2 O 2 , but not ATP. SS rats fed a HS diet for 3 weeks demonstrated impaired NO production; the response to Ang II or H 2 O 2 on HS contained only 23.7±6.6 and 43.4±28.4% of total effects on LS, respectively ( P <0.05). Therefore, when fed a HS diet, SS podocytes had an impaired NO response to Ang II or oxidative stress, suggesting that NO signaling is dysfunctional and likely contributes to the development of kidney injury.

scholarly journals RAP2.3 negatively regulates nitric oxide biosynthesis and related responses through a rheostat-like mechanism in Arabidopsis

2020 ◽  
Vol 71 (10) ◽  
pp. 3157-3171 ◽  
Author(s):  
José León ◽  
Álvaro Costa-Broseta ◽  
Mari Cruz Castillo
Keyword(s):  
Nitric Oxide ◽  
Root Elongation ◽  
Guard Cells ◽  
No Production ◽  
Aba Signaling ◽  
Inhibition Of Growth ◽  
Genome Wide ◽  
Molecular Rheostat ◽  
No Signaling

Abstract Nitric oxide (NO) is sensed through a mechanism involving the degradation of group-VII ERF transcription factors (ERFVIIs) that is mediated by the N-degron pathway. However, the mechanisms regulating NO homeostasis and downstream responses remain mostly unknown. To explore the role of ERFVIIs in regulating NO production and signaling, genome-wide transcriptome analyses were performed on single and multiple erfvii mutants of Arabidopsis following exposure to NO. Transgenic plants overexpressing degradable or non-degradable versions of RAP2.3, one of the five ERFVIIs, were also examined. Enhanced RAP2.3 expression attenuated the changes in the transcriptome upon exposure to NO, and thereby acted as a brake for NO-triggered responses that included the activation of jasmonate and ABA signaling. The expression of non-degradable RAP2.3 attenuated NO biosynthesis in shoots but not in roots, and released the NO-triggered inhibition of hypocotyl and root elongation. In the guard cells of stomata, the control of NO accumulation depended on PRT6-triggered degradation of RAP2.3 more than on RAP2.3 levels. RAP2.3 therefore seemed to work as a molecular rheostat controlling NO homeostasis and signaling. Its function as a brake for NO signaling was released upon NO-triggered PRT6-mediated degradation, thus allowing the inhibition of growth, and the potentiation of jasmonate- and ABA-related signaling.

scholarly journals Glucose release as a response to glucagon in rat hepatocyte culture: involvement of NO signaling

2008 ◽  
pp. 569-575
Author(s):  
H Farghali ◽  
J Hodis ◽  
N Kutinová-Canová ◽  
P Potměšil ◽  
E Kmoníčková ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Glycogen Synthase ◽  
Inos Mrna ◽  
No Production ◽  
Rat Hepatocyte ◽  
No Donor ◽  
Glucagon Receptor ◽  
Nos Inhibitors ◽  
No Signaling ◽  
Rat Hepatocyte Culture

Glucagon and α-adrenergic-induced glycogenolysis is realized via the agonist/adenylyl cyclase/cAMP/protein kinase signaling pathway or via the activation of phosphorylase kinase by the mobilized calcium that supports the inhibition of glycogen synthase, respectively. The role of nitric oxide (NO) in this process has not been extensively studied. The present work was directed to the question whether NO is produced during glucagon-induced glycogenolysis in rat hepatocyte in a similar way like α-adrenoceptor stimulation. Glycogen-rich hepatocyte cultures were used. NO production (NO2-) was assessed under the influence of glucagon, dibutyryl cyclic AMP (db-cAMP), forskolin, the nitric oxide synthase (NOS) inhibitors Nω-nitro-Larginine methyl ester (L-NAME) and aminoguanidine, and the NO donor S-nitroso-N-acetyl penicillamine (SNAP). Inducible NOS (iNOS) mRNA was examined by reverse transcription-polymerase chain reaction. Glycogenolysis was followed up by estimation of medium glucose levels. The amount of glucose and NO2 - released by glycogen-rich hepatocytes was increased as a result of glucagon, db-cAMP, forskolin and SNAP treatments. iNOS gene expression was upregulated by glucagon. Glycogenolysis that occurs through glucagon receptor stimulation involves NO production downstream of transduction pathways through an isoform of NO synthase. The present and previous studies document possible involvement of NO signaling in glycogenolytic response to glucagon and adrenergic agonists in hepatocytes.

scholarly journals Spermine and L-Name Pretreatment Effects on Polyamine and Nitric Oxide Metabolism in Rat Brain During Seizures

2007 ◽  
Vol 26 (3) ◽  
pp. 220-226
Author(s):  
Ivana Stojanović ◽  
Ankica Jelenković ◽  
Ivana Vasiljević ◽  
Dušica Pavlović ◽  
Gordana Bjelaković
Keyword(s):  
Nitric Oxide ◽  
Rat Brain ◽  
Polyamine Metabolism ◽  
No Production ◽  
Protective Effects ◽  
Signaling System ◽  
Activity Increase ◽  
Nitric Oxide Metabolism ◽  
No Signaling ◽  
Pretreatment Effects

Spermine and L-Name Pretreatment Effects on Polyamine and Nitric Oxide Metabolism in Rat Brain During SeizuresIn the CNS polyamines can exert opposite effects, depending on the concentration and conditions in the cell. Protective or neurotoxic polyamine effects were documented during seizures and repeated CNS excitation. Intensive research of exogenous polyamines effects during seizures induced by numerous agents did not clear up confusions about the duality of effects and the role of polyamines in seizures. In order to understand polyamine modulatory effects in seizures, the importance of NO and polyamine metabolism interdependence and the possible implication of changes of postulated NO and polyamine equillibrium in seizures, the effects of spermine alone and in combination with L-NAME (NOS inhibitor) on seizures induced by pentazol (PTZ) were investigated. To compare the obtained results, the effects of anticonvulsant midazolam on NO production during seizures were also investigated. Seizures were induced by i.p. application of pentazol (100 mg/kg b.w.). Spermine and L-NAME were administered i.p. before PTZ. In the striatum and hippocampus, spermine induced increased NO production (p<0.001) related to values in the group treated by PTZ. Application of L-NAME before spermine and PTZ caused decrease of NO production in comparison with animals treated only by PTZ or spermine and PTZ. L-NAME given before spermine exerts protective effects related to seizures induced by PTZ and to the group treated by spermine, extending the time of seizure symptoms appearance, thus confirming the NO signaling system involvement in spermine effects during seizures. Highly significant PAO activity increase caused by spermine points out the intensified interconversion of spermine into putrescine, in order to maintain the intracellular putrescine concentration. The obtained results prove a strong relationship between the NO signaling system and polyamine metabolism in the brain during seizures and the importance of their changes in this kind of CNS injury.

Chronic hypertension impairs flow-induced vasodilation and augments the myogenic response in fetal lung

2002 ◽  
Vol 282 (1) ◽  
pp. L56-L66 ◽  
Author(s):  
Laurent Storme ◽  
Thomas A. Parker ◽  
John P. Kinsella ◽  
Robyn L. Rairigh ◽  
Steven H. Abman
Keyword(s):  
Nitric Oxide ◽  
Ductus Arteriosus ◽  
Fetal Lung ◽  
No Synthase ◽  
Chronic Hypertension ◽  
No Production ◽  
Myogenic Response ◽  
Hemodynamic Effects ◽  
No Signaling ◽  
Synthase Inhibitor

We hypothesized that altered vasoreactivity in perinatal pulmonary hypertension (PH) is characterized by abnormal responses to hemodynamic stress, including the loss of flow-induced vasodilation and an augmented myogenic response. Therefore, we studied the acute hemodynamic effects of brief compression of the ductus arteriosus (DA) in control fetal lambs and in lambs during exposure to chronic PH. In both groups, acute DA compression decreased pulmonary vascular resistance (PVR) by 20% at baseline ( day 0). After 2 days of hypertension, acute DA compression paradoxically increased PVR by 50% in PH lambs, whereas PVR decreased by 25% in controls. During the 8-day study period, PVR increased during acute DA compression in PH lambs, whereas acute DA compression continued to cause vasodilation in controls. Brief treatment with the nitric oxide (NO) synthase inhibitor nitro-l-arginine (l-NA) increased basal PVR in control but not PH lambs, suggesting decreased NO production in PH lambs. Chronic hypertension increased the myogenic response afterl-NA in PH lambs, whereas the myogenic response remained unchanged in controls. The myogenic response was inhibited by nifedipine in PH lambs, suggesting that the myogenic response is dependent upon the influx of extracellular calcium. We conclude that chronic PH impairs flow-induced vasodilation and increases the myogenic response in fetal lung. We speculate that decreased NO signaling and an augmented myogenic response contributes to abnormal vasoreactivity in PH.

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