scholarly journals Alterations in Nitric Oxide and Endothelin-1 Bioactivity Underlie Cerebrovascular Dysfunction in ApoE-Deficient Mice

2010 ◽  
Vol 30 (8) ◽  
pp. 1494-1503 ◽  
Author(s):  
Kazuo Yamashiro ◽  
Alexandra B Milsom ◽  
Johan Duchene ◽  
Catherine Panayiotou ◽  
Takao Urabe ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Phosphodiesterase Inhibitor ◽  
No Production ◽  
Endothelin 1 ◽  
Cerebrovascular Dysfunction ◽  
Enos Phosphorylation ◽  
No Bioavailability ◽  
Deficient Mice

Hypercholesterolemia is associated with decreased nitric oxide (NO) bioavailability and endothelial dysfunction, a phenomenon thought to have a major role in the altered cerebral blood flow evident in stroke. Therefore, strategies that increase endothelial NO production have potential utility. Vascular reactivity of the middle cerebral artery (MCA) from C57BL/6J wild-type (WT) mice, apolipoprotein-E knockout (ApoE−/−) mice, and mice treated with the phosphodiesterase inhibitor cilostazol (100 mg/kg) was analyzed using the tension myograph. Contractile responses to endothelin-1 were significantly enhanced in MCA from ApoE−/− mice compared with WT mice ( P<0.01), an effect absent in cilostazol-treated ApoE−/− mice. Acetylcholine-induced relaxation (which is entirely NO-dependent) was significantly impaired in MCA of ApoE−/− mice compared with WT mice ( P<0.05), again an effect prevented by cilostazol treatment. Endothelial NOS phosphorylation at Ser1179 was decreased in the aorta of ApoE−/− mice compared with WT mice ( P<0.05), an effect normalized by cilostazol. Taken together, our data suggest that the endothelial dysfunction observed in MCA associated with hypercholesterolemia is prevented by cilostazol, an effect likely due to the increase in eNOS phosphorylation and, therefore, activity.

Microparticles from Patients with the Acute Coronary Syndrome Impair Vasodilatation by Inhibiting the Akt/eNOS-Hsp90 Signaling Pathway

Cardiology ◽  
2015 ◽  
Vol 132 (4) ◽  
pp. 252-260 ◽  
Author(s):  
Wen-Qi Han ◽  
Feng-Jun Chang ◽  
Qun-Rang Wang ◽  
Jun-Qiang Pan
Keyword(s):  
Nitric Oxide ◽  
Acute Coronary Syndrome ◽  
Endothelial Dysfunction ◽  
Heat Shock Protein 90 ◽  
No Production ◽  
Healthy Controls ◽  
Coronary Syndrome ◽  
Enos Phosphorylation ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Objectives: Endothelial dysfunction is involved in the development of the acute coronary syndrome (ACS). Plasma microparticles (MPs) from other diseases have been demonstrated to initiate coagulation and endothelial dysfunction. However, whether MPs from ACS patients impair vasodilatation and endothelial function remains unclear. Methods: Patients (n = 62) with ACS and healthy controls (n = 30) were recruited for MP isolation. Rat thoracic aortas were incubated with MPs from ACS patients or healthy controls to determine the effects of MPs on endothelial-dependent vasodilatation, the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), the interaction of eNOS with heat shock protein 90 (Hsp90), and nitric oxide (NO) and superoxide anion (O2-) production. The origin of MPs was assessed by flow cytometry. Results: MP concentrations were increased in patients with ACS compared with healthy controls. They were positively correlated with the degree of coronary artery stenosis. MPs from ACS patients impair endothelial-dependent vasodilatation, decrease both Akt and eNOS phosphorylation, decrease the interaction between eNOS and Hsp90, and decrease NO production but increase O2- generation in rat thoracic aortas. Endothelial-derived MPs and platelet-derived MPs made up nearly 75% of MPs. Conclusions: Our data indicate that MPs from ACS patients negatively affect endothelial-dependent vasodilatation via Akt/eNOS-Hsp90 pathways.

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

2011 ◽  
Vol 300 (6) ◽  
pp. R1288-R1295 ◽  
Author(s):  
Stephane L. Bourque ◽  
Sandra T. Davidge ◽  
Michael A. Adams
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Disease ◽  
Vascular Remodeling ◽  
Vascular Function ◽  
No Synthase ◽  
Endothelin 1 ◽  
No Signaling ◽  
No Bioavailability

Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease. Here, we review classical and more recent data that suggest that ET-1 should be regarded as an essential component of NO signaling. In particular, we review evidence of the role of ET-1 in models of acute and chronic NO synthase blockade. Furthermore, we discuss the possible mechanisms by which NO modulates ET-1 activity. On the basis of these studies, we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.

Abstract 479: Orotic Acid Induces Hypertension Associated With Impaired Endothelial Nitric Oxide Synthesis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
You-Jin Choi ◽  
Byung-Hoon Lee
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Protein Kinase ◽  
Endothelial Dysfunction ◽  
Orotic Acid ◽  
No Production ◽  
Model Assessment ◽  
Enos Phosphorylation ◽  
Orotic Aciduria ◽  
In Cells

Orotic acid (OA) is an intermediate of pyrimidine nucleotide biosynthesis. Hereditary deficiencies in some enzymes associated with pyrimidine synthesis or the urea cycle induce OA accumulation, resulting in orotic aciduria. A link between patients with orotic aciduria and hypertension has been reported; however, the molecular mechanisms remain elusive. In this study, to elucidate the role of OA in vascular insulin resistance, we investigated whether OA induced endothelial dysfunction and hypertension. OA inhibited insulin- or metformin-stimulated nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation in human umbilical vein endothelial cells (HUVEC). A decreased insulin response by OA was mediated by impairment of the insulin-stimulated phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling pathway in cells overexpressing the p110-PI3K catalytic subunit. Impaired effects of metformin on eNOS phosphorylation and NO production were reversed in cells transfected with constitutively active AMP-activated protein kinase. Moreover, experimental induction of orotic aciduria in rats caused insulin resistance, measured as a 125% increase in the homeostasis model assessment, and hypertension, measured as a 25% increase in systolic blood pressure. OA increased the plasma concentration of endothelin-1 by 201% and significantly inhibited insulin- or metformin-induced vasodilation. A compromised insulin or metformin response on the Akt/eNOS and AMPK/eNOS pathway was observed in aortic rings of OA-fed rats. Taken together, we showed that OA induces endothelial dysfunction by contributing to vascular and systemic insulin resistance that affects insulin- or metformin-induced NO production, leading to the development of hypertension.

Decreased NO Bioavailability Leading to Endothelial Dysfunction in Children with ALL Results From Increased eNOS Inhibiting by Asymmetrical Dimethylarginine and May Be Associated with Increased Mortality

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5318-5318
Author(s):  
Julita Porwolik ◽  
Ewa Niedzielska ◽  
Adrian Doroszko ◽  
Alicja Piasecka-Grzeszek ◽  
Urszula Solska ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Conflicts Of Interest ◽  
Control Group ◽  
Healthy Children ◽  
Asymmetrical Dimethylarginine ◽  
Plasma Adma ◽  
No Bioavailability ◽  
Endothelial Nitric Oxide

Abstract Abstract 5318 Background Endothelial dysfunction worsens the prognosis in numerous severe diseases. Impaired vascular reactivity, increased procoagulative and proinflammatory action are commonly observed when the nitric oxide bioavailability is limited. Asymmetrical dimethylarginine (ADMA) is a competive inhibitor of the endothelial nitric oxide synthase (eNOS). ADMA is produced during proteolysis of methylated proteins, especially histones. The aim this study was to determine if ADMA may play important role in pathogenesis of endothelial dysfunction in children with ALL. Material and Methods N=14 children at age of 4–18 years with ALL treated with the ALLIC protocol were investigated. Plasma levels of the NO pathway metabolites (L-Arginine, ADMA) were analyzed at baseline, then during the 33rd and 78th day of protocol. The control group constituted of N=14, age-matched healthy children. Results Plasma ADMA levels were significantly higher in children with ALL at baseline as compared to the control group (1.92±0.42 vs. 0.56±0.1 ng/ml, p<0.05), and were significantly decreasing to 0.63±0.15ng/ml, p<0.05 following the steroid therapy. During the 78th day the ADMA levels were maintained at similar levels as compared to the 33rd day. Opposite trends were observed with the L-Arginine levels and the L-Arg/ADMA ratio reflecting the NO synthesis. L-Arg and L-Arg/ADMA ratio were significantly lower in children with ALL at baseline vs. control group (41.65±4.12vs.52.4±2.31pg/ml and 28.7±6.61vs.83.41±14.13, respectively, p<0.05). Moreover, the L-Arg/ADMA ratio at the 78th day was significantly higer in cases treated unsuccesfully in comparison with those who survived (88.1±21.3vs.43.0±10.2, p<0.05). Conclusions Decreased NO bioavailability in children with ALL at baseline results from the eNOS inhibiting by ADMA and may be associated with increased mortality. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis

2019 ◽  
Vol 126 (1) ◽  
pp. 60-66 ◽  
Author(s):  
Jin Hee Jeong ◽  
Nichole Lee ◽  
Matthew A. Tucker ◽  
Paula Rodriguez-Miguelez ◽  
Jacob Looney ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cystic Fibrosis ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Function ◽  
Genetic Disorder ◽  
No Production ◽  
Vascular Endothelial ◽  
Vascular Endothelial Function ◽  
No Bioavailability

Cystic fibrosis (CF) is a genetic disorder associated with vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function, and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. Twenty-nine patients with CF (18 ± 8 yr old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received a 5 mg/kg dose of oral BH4 (BH4-5; n = 17) or a 20 mg/kg dose of oral BH4 (BH4-20; n = 12). On a separate visit, a subset of patients from each group was retested following a placebo (PLC; n = 9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function, and a plasma sample was obtained before and 3 h after treatment. Cultured endothelial cells were treated with plasma to assess NO bioavailability. Baseline FMD was lower in patients compared with controls (5.7 ± 3.4 vs. 8.4 ± 3.5%, respectively, P = 0.005). No change in FMD was observed following PLC or BH4-5 (∆FMD: −0.8 ± 1.9% and −0.5 ± 2.5%; P = 0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in significant improvements in FMD (∆FMD: 1.1 ± 1.4%) compared with BH4-5 ( P = 0.023) and PLC ( P = 0.017). Moreover, BH4-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH4 at 20 mg/kg improves vascular endothelial function in patients with CF, likely via increased endothelial NO synthase coupling. These findings support the hypothesis that loss of BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF. NEW & NOTEWORTHY For the first time, the present study documents that a single dose of oral BH4 can improve vascular endothelial function in patients with cystic fibrosis (CF), and our in vitro data suggest this is via decreasing uncoupled nitric oxide. These data provide insight into the important role of BH4 bioactivity in vascular dysfunction and provide the foundation for further investigation into the chronic effects of BH4 treatment in patients with CF.

scholarly journals Modulation of Vasodilator Response via the Nitric Oxide Pathway after Acute Methyl Mercury Chloride Exposure in Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
S. Omanwar ◽  
B. Saidullah ◽  
K. Ravi ◽  
M. Fahim
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Methyl Mercury ◽  
Vascular Reactivity ◽  
Mercury Chloride ◽  
No Production ◽  
Vasodilator Response ◽  
No Bioavailability ◽  
Chloride Treatment ◽  
Oxide Synthase

Mercury exposure induces endothelial dysfunction leading to loss of endothelium-dependent vasorelaxation due to decreased nitric oxide (NO) bioavailability via increased oxidative stress. Our aim was to investigate whether acute treatment with methyl mercury chloride changes the endothelium-dependent vasodilator response and to explore the possible mechanisms behind the observed effects. Wistar rats were treated with methyl mercury chloride (5 mg/kg,po.). The methyl mercury chloride treatment resulted in an increased aortic vasorelaxant response to acetylcholine (ACh). In methyl-mercury-chloride-exposed rats, the % change in vasorelaxant response of ACh in presence of Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME;10-4 M) was significantly increased, and in presence of glybenclamide (10-5 M), the response was similar to that of untreated rats, indicating the involvement of NO and not of endothelium-derived hyperpolarizing factor (EDHF). In addition, superoxide dismutase (SOD) + catalase treatment increased the NO modulation of vasodilator response in methyl-mercury-chloride-exposed rats. Our results demonstrate an increase in the vascular reactivity to ACh in aorta of rats acutely exposed to methyl mercury chloride. Methyl mercury chloride induces nitric oxide synthase (NOS) and increases the NO production along with inducing oxidative stress without affecting the EDHF pathway.

Activated pericyte attenuates endothelial functions: nitric oxide – cGMP rescues activated pericyte-associated endothelial dysfunctions

2007 ◽  
Vol 85 (6) ◽  
pp. 709-720 ◽  
Author(s):  
Syamantak Majumder ◽  
K. P. Tamilarasan ◽  
Gopi Krishna Kolluru ◽  
Ajit Muley ◽  
C. Madhavan Nair ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Phosphodiesterase Inhibitor ◽  
Egg Yolk ◽  
No Production ◽  
Dependent Manner ◽  
Endothelium Dysfunction ◽  
Vascular Bed

Hepatic stellate cells are liver-specific pericytes and exist in close proximity with endothelial cells. The activation of liver pericytes is intrinsic to liver pathogenesis, and leads to endothelial dysfunction, including the low bioavailability of nitric oxide (NO). However, the role of nitric oxide in pericyte–endothelium cross-talk has not yet been elucidated. This work examines the cellular mechanism of action of NO in pericyte-mediated endothelial dysfunction. We used in vitro coculture and conditioned medium systems to study the effects of activated liver pericytes on endothelial function, and an egg yolk vascular bed model was used to study the effects of activated pericytes on angiogenesis. This study also demonstrates that activated pericytes attenuate the migration, proliferation, permeability, and NO production of endothelial cells. Our results demonstrate that activated pericytes restrict angiogenesis in egg yolk vascular bed models, and NO supplementation recovers 70% of the inhibition. Our results also demonstrate that supplementation with NO, sildenafil citrate (phosphodiesterase inhibitor), and 8-bromo-cGMP (cGMP analog) partially recovers activated-pericyte-mediated endothelium dysfunction. We conclude that NO–cGMP alleviates activated-pericyte-associated endothelial dysfunction, including angiogenesis, in a cGMP-dependent manner.

Mesenteric arteries from stroke-prone spontaneously hypertensive rats exhibit an increase in nitric-oxide-dependent vasorelaxation

2018 ◽  
Vol 96 (8) ◽  
pp. 719-727 ◽  
Author(s):  
Brandi M. Wynne ◽  
Hicham Labazi ◽  
Victor V. Lima ◽  
Fernando S. Carneiro ◽  
R. Clinton Webb ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Spontaneously Hypertensive Rat ◽  
No Synthase ◽  
Mesenteric Arteries ◽  
Maximum Effect ◽  
No Production ◽  
Primary Role ◽  
Spontaneously Hypertensive

The endothelium is crucial for the maintenance of vascular tone by releasing several vasoactive substances, including nitric oxide (NO). Systemic mean arterial pressure is primarily regulated by the resistance vasculature, which has been shown to exhibit increased vascular reactivity, and decreased vasorelaxation during hypertension. Here, we aimed to determine the mechanism for mesenteric artery vasorelaxation of the stroke-prone spontaneously hypertensive rat (SHRSP). We hypothesized that endothelial NO synthase (eNOS) is upregulated in SHRSP vessels, increasing NO production to compensate for the endothelial dysfunction. Concentration–response curves to acetylcholine (ACh) were performed in second-order mesenteric arteries; we observed decreased relaxation responses to ACh (maximum effect elicited by the agonist) as compared with Wistar-Kyoto (WKY) controls. Vessels from SHRSP incubated with Nω-nitro-l-arginine methyl ester and (or) indomethacin exhibited decreased ACh-mediated relaxation, suggesting a primary role for NO-dependent relaxation. Vessels from SHRSP exhibited a significantly decreased relaxation response with inducible NO synthase (iNOS) inhibition, as compared with WKY vessels. Western blot analysis showed increased total phosphorylated NF-κB, and phosphorylated and total eNOS in SHRSP vessels. Overall, these data suggest a compensatory role for NO by increased eNOS activation. Moreover, we believe that iNOS, although increasing NO bioavailability to compensate for decreased relaxation, leads to a cycle of further endothelial dysfunction in SHRSP mesenteric arteries.

scholarly journals Impairment of autophagy in endothelial cells prevents shear-stress-induced increases in nitric oxide bioavailability

2014 ◽  
Vol 92 (7) ◽  
pp. 605-612 ◽  
Author(s):  
Leena P. Bharath ◽  
Robert Mueller ◽  
Youyou Li ◽  
Ting Ruan ◽  
David Kunz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Oxidant Stress ◽  
Critical Role ◽  
No Production ◽  
Enos Phosphorylation ◽  
Autophagy Pathway ◽  
No Bioavailability ◽  
Static Conditions

Autophagy is a lysosomal catabolic process by which cells degrade or recycle their contents to maintain cellular homeostasis, adapt to stress, and respond to disease. Impairment of autophagy in endothelial cells studied under static conditions results in oxidant stress and impaired nitric oxide (NO) bioavailability. We tested the hypothesis that vascular autophagy is also important for induction of NO production caused by exposure of endothelial cells to shear stress (i.e., 3 h × ≈20 dyn/cm2). Atg3 is a requisite autophagy pathway mediator. Control cells treated with non-targeting control siRNA showed increased autophagy, reactive oxygen species (ROS) production, endothelial NO synthase (eNOS) phosphorylation, and NO production upon exposure to shear stress (p < 0.05 for all). In contrast, cells with >85% knockdown of Atg3 protein expression (via Atg3 siRNA) exhibited a profound impairment of eNOS phosphorylation, and were incapable of increasing NO in response to shear stress. Moreover, ROS accumulation and inflammatory cytokine production (MCP-1 and IL-8) were exaggerated (all p < 0.05) in response to shear stress. These findings reveal that autophagy not only plays a critical role in maintaining NO bioavailability, but may also be a key regulator of oxidant–antioxidant balance and inflammatory–anti-inflammatory balance that ultimately regulate endothelial cell responses to shear stress.

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

2007 ◽  
Vol 293 (2) ◽  
pp. R707-R713 ◽  
Author(s):  
Sharyn M. Fitzgerald ◽  
Barbara K. Kemp-Harper ◽  
Helena C. Parkington ◽  
Geoffrey A. Head ◽  
Roger G. Evans
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Arterial Pressure ◽  
Early Stage ◽  
Mesenteric Arteries ◽  
No Production ◽  
Wild Type ◽  
Early Diabetes ◽  
Diabetes In Mice ◽  
Vehicle Treatment

We determined whether nitric oxide (NO) counters the development of hypertension at the onset of diabetes in mice, whether this is dependent on endothelial NO synthase (eNOS), and whether non-NO endothelium-dependent vasodilator mechanisms are altered in diabetes in mice. Male mice were instrumented for chronic measurement of mean arterial pressure (MAP). In wild-type mice, MAP was greater after 5 wk of Nω-nitro-l-arginine methyl ester (l-NAME; 100 mg·kg−1·day−1 in drinking water; 97 ± 3 mmHg) than after vehicle treatment (88 ± 3 mmHg). MAP was also elevated in eNOS null mice (113 ± 4 mmHg). Seven days after streptozotocin treatment (200 mg/kg iv) MAP was further increased in l-NAME-treated mice (108 ± 5 mmHg) but not in vehicle-treated mice (88 ± 3 mmHg) nor eNOS null mice (104 ± 3 mmHg). In wild-type mice, maximal vasorelaxation of mesenteric arteries to acetylcholine was not altered by chronic l-NAME or induction of diabetes but was reduced by 42 ± 6% in l-NAME-treated diabetic mice. Furthermore, the relative roles of NO and endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced vasorelaxation were altered; the EDHF component was enhanced by l-NAME and blunted by diabetes. These data suggest that NO protects against the development of hypertension during early-stage diabetes in mice, even in the absence of eNOS. Furthermore, in mesenteric arteries, diabetes is associated with reduced EDHF function, with an apparent compensatory increase in NO function. Thus, prior inhibition of NOS results in endothelial dysfunction in early diabetes, since the diabetes-induced reduction in EDHF function cannot be compensated by increases in NO production.

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