Abstract 16718: Energy Induced Vasodilation in a Model of Endothelial Dysfunction Requires Nitric Oxide

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Brian Lindemer ◽  
Dorothee Weihrauch ◽  
Agnes Keszler ◽  
Nicole Lohr
Keyword(s):  
Endothelial Dysfunction ◽  
Dark Period ◽  
Limb Ischemia ◽  
Vessel Diameter ◽  
No Production ◽  
Flow Mediated Dilation ◽  
Impaired Wound Healing ◽  
Nos Inhibitor ◽  
No Bioavailability ◽  
Artery Disease

Introduction: Over 8 million Americans are treated for peripheral artery disease (PAD), i.e. intermittent claudication, impaired wound healing, and critical limb ischemia. Endothelial dysfunction of the microcirculation is a potential mechanism for the pathogenesis of PAD because risk factors for PAD- age, hypertension, atherosclerosis, diabetes mellitus, and active tobacco use, have been directly related to a reduction in NOS expression and NO production. These reductions in NO bioavailability impair flow mediated dilation of the brachial artery and acetylcholine induced vasodilation. We have shown energy (670 nm (R/NIR)) can increase NO independent of NOS through release of NO from nitrosyl-heme stores. We hypothesized R/NIR can stimulate vasodilation, and serve as a potential therapy to recover vasodilation in a model of endothelial dysfunction (db/db mice). Methods: Human dermal microvascular endothelial cells (HMVEC) loaded with DAF-2 were stimulated with R/NIR 100mW/cm2 up to 6J. NO was measured using HPLC of DAF-2T. To test vasodilation, facial arteries from C57Bl/6 and db/db mice were isolated, pressurized to 60mmHg, and pre-constricted with U46619. The vessels were irradiated with 670 nm light (10mW/cm2) for 5 min with 10 min dark period between irradiation. Results: HMVEC stimulated with R/NIR increased NO 28.3% (±11.2, p<0.05). The NO scavenger c-PTIO inhibited R/NIR (17.0%±5.9, p<0.05) but was unchanged by pre-incubation with NOS inhibitor L-NAME (1mM) (13.1% ± 5.6). Vessel diameter increased up to 17.8% (±3, p<0.05) after 5 min with R/NIR. L-NAME did not affect dilation (13.74% ±2.2), however c-PTIO (100μM) could attenuate dilation (-.51% ± 1.1, p<0.001). R/NIR vasodilation was abolished with vessel denudation (1.2%± 2.21, p<0.001), suggesting R/NIR dilation was endothelial dependent. Impaired dilation in db/db mice was reversed, as R/NIR could significantly dilate db/db vessels after 5 min [(13.7% ± 2.8) vs. control (17.8% ±3)]. Conclusion: R/NIR vasodilation requires intact endothelium and NO, but does not require NOS. In an obesity model of endothelial dysfunction, R/NIR can significantly restore vasodilation. Therefore, R/NIR as a source for therapeutic NO should be strongly considered in the treatment of ischemic wounds.

CD14+CD16++ “nonclassical” monocytes are associated with endothelial dysfunction in patients with coronary artery disease

2017 ◽  
Vol 117 (05) ◽  
pp. 971-980 ◽  
Author(s):  
Karol Urbanski ◽  
Dominik Ludew ◽  
Grzegorz Filip ◽  
Magdalena Filip ◽  
Agnieszka Sagan ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mononuclear Cells ◽  
Vascular Dysfunction ◽  
Activation Markers ◽  
Mammary Arteries ◽  
No Bioavailability ◽  
Artery Disease

SummaryEndothelial dysfunction and inflammation are key mechanisms of vascular disease. We hypothesised that heterogeneity of monocyte subpopulations may be related to the development of vascular dysfunction in coronary artery disease (CAD). Therefore, we examined the relationships between monocyte subsets (CD14++CD16– “classical – Mon1”, CD14++CD16+ “intermediate – Mon2” and CD14+CD16++ “nonclassical – Mon3”), endothelial function and risk factor profiles in 130 patients with CAD undergoing coronary artery bypass grafting. This allowed for direct nitric oxide (NO) bioavailability assessment using isometric tension studies ex vivo (acetylcholine; ACh- and sodium- nitropruside; SNP-dependent) in segments of internal mammary arteries. The expression of CD14 and CD16 antigens and activation markers were determined in peripheral blood mononuclear cells using flow cytometry. Patients with high CD14+CD16++ “nonclassical” and low CD14++CD16- “classical” monocytes presented impaired endothelial function. High frequency of CD14+CD16++ “nonclassical” monocytes was associated with increased vascular superoxide production. Furthermore, endothelial dysfunction was associated with higher expression of activation marker CD11c selectively on CD14+CD16++ monocytes. Nonclassical and classical monocyte frequencies remained independent predictors of endothelial dysfunction when major risk factors for atherosclerosis were taken into account (β =0.18 p=0.04 and β =-0.19 p=0.03, respectively). In summary, our data indicate that CD14+CD16++ “nonclassical” monocytes are associated with more advanced vascular dysfunction measured as NO-bioavailability and vascular reactive oxygen species production.

scholarly journals Abnormal Microvascular Architecture, Fibrosis, and Pericyte Characteristics in the Calf Muscle of Peripheral Artery Disease Patients with Claudication and Critical Limb Ischemia

2020 ◽  
Vol 9 (8) ◽  
pp. 2575
Author(s):  
Constance J. Mietus ◽  
Timothy J. Lackner ◽  
Petros S. Karvelis ◽  
Gregory T. Willcockson ◽  
Christina M. Shields ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Stage Iv ◽  
Limb Ischemia ◽  
Vessel Diameter ◽  
Calf Muscle ◽  
Stage Ii ◽  
Vascular Pathology ◽  
Peripheral Artery ◽  
Microvascular Architecture ◽  
Artery Disease

Work from our laboratory documents pathological events, including myofiber oxidative damage and degeneration, myofibrosis, micro-vessel (diameter = 50–150 μm) remodeling, and collagenous investment of terminal micro-vessels (diameter ≤ 15 µm) in the calf muscle of patients with Peripheral Artery Disease (PAD). In this study, we evaluate the hypothesis that the vascular pathology associated with the legs of PAD patients encompasses pathologic changes to the smallest micro-vessels in calf muscle. Biopsies were collected from the calf muscle of control subjects and patients with Fontaine Stage II and Stage IV PAD. Slide specimens were evaluated by Quantitative Multi-Spectral and Fluorescence Microscopy. Inter-myofiber collagen, stained with Masson Trichrome (MT), was increased in Stage II patients, and more substantially in Stage IV patients in association with collagenous thickening of terminal micro-vessel walls. Evaluation of the Basement Membrane (BM) of these vessels reveals increased thickness in Stage II patients, and increased thickness, diameter, and Collagen I deposition in Stage IV patients. Coverage of these micro-vessels with pericytes, key contributors to fibrosis and BM remodeling, was increased in Stage II patients, and was greatest in Stage IV patients. Vascular pathology of the legs of PAD patients extends beyond atherosclerotic main inflow arteries and affects the entire vascular tree—including the smallest micro-vessels.

Paradoxical hypotension following increased hematocrit and blood viscosity

2005 ◽  
Vol 289 (5) ◽  
pp. H2136-H2143 ◽  
Author(s):  
Judith Martini ◽  
Benoît Carpentier ◽  
Adolfo Chávez Negrete ◽  
John A. Frangos ◽  
Marcos Intaglietta
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Blood Viscosity ◽  
Exchange Transfusion ◽  
Vessel Diameter ◽  
No Production ◽  
Packed Red Blood Cells ◽  
Arterial Blood ◽  
Nos Inhibitor ◽  
Window Chamber

Hematocrit (Hct) of awake hamsters and CD-1 mice was acutely increased by isovolemic exchange transfusion of packed red blood cells (RBCs) to assess the relation between Hct and blood pressure. Increasing Hct 7–13% of baseline decreased mean arterial blood pressure (MAP) by 13 mmHg. Increasing Hct above 19% reversed this trend and caused MAP to rise above baseline. This relationship is described by a parabolic function ( R2 = 0.57 and P < 0.05). Hamsters pretreated with the nitric oxide (NO) synthase (NOS) inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) and endothelial NOS-deficient mice showed no change in MAP when Hct was increased by <19%. Nitrate/nitrite plasma levels of Hct-augmented hamsters increased relative to control and l-NAME treated animals. The blood pressure effect was stable 2 h after exchange transfusion. These findings suggest that increasing Hct increases blood viscosity, shear stress, and NO production, leading to vasodilation and mild hypotension. This was corroborated by measuring A1 arteriolar diameters (55.0 ± 21.5 μm) and blood flow in the hamster window chamber preparation, which showed statistically significant increased vessel diameter (1.04 ± 0.1 relative to baseline) and microcirculatory blood flow (1.39 ± 0.68 relative to baseline) after exchange transfusion with packed RBCs. Larger increases of Hct (>19% of baseline) led blood viscosity to increase >50%, overwhelming the NO effect through a significant viscosity-dependent increase in vascular resistance, causing MAP to rise above baseline values.

scholarly journals Correlation of Brachial Flow Mediated Dilation with Severity of Coronary Artery Disease

2014 ◽  
pp. 71-8
Author(s):  
Erwin Mulia ◽  
Ismoyo Sunu ◽  
Andang H Joesoef, ◽  
Ganesja M Harimurti
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Negative Correlation ◽  
Morphological Changes ◽  
Atherosclerotic Lesion ◽  
Flow Mediated Dilation ◽  
Gensini Score ◽  
Cross Sectional ◽  
Artery Disease

Background. Endothelial dysfunction precedes the development of morphological changes and contributes to atherosclerotic lesion development and progression. Evaluation using non invasive method such as brachial FMD (flow mediated dilation) has given inconsistent information for extension and coronary atherosclerotic severity regarding endothelial dysfunction. This research will evaluate the correlation between brachial FMD and severity of coronary artery disease (CAD) stenosis.Methods. It was a cross sectional study. Evaluations were performed in 85 patients who had followed elective coronary angiography and fulfilled inclusion criteria in National Cardiovascular Center Harapan Kita since January until October of 2012. Correlation between brachial FMD and severity of CAD stenosis (Gensini score) was evaluated using linear regression analysis.Results. Brachial FMD had negative correlation with Gensini score (R= -0,227; P= 0,037). Hypertension had negative correlation with brachial FMD (R= -0,235; P= 0,032). Male gender had positive correlation with brachial FMD (R= 0,220; P= 0,040).Conclusion. There was weak negative correlation between brachial FMD and Gensini score.

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.

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.

Abstract P342: Sirt 1 on Endothelial Dysfunction in Small Arteries From Obese Patients

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Agostino Virdis ◽  
Stefano Masi ◽  
Monica Nannipieri ◽  
Daniela Guarino ◽  
Marco Anselmino ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Subcutaneous Tissue ◽  
Normal Weight ◽  
No Production ◽  
Laparoscopic Bariatric Surgery ◽  
Obese Patients ◽  
Resistance Arteries ◽  
Small Arteries ◽  
Small Resistance ◽  
No Bioavailability

Obesity is associated with endothelial dysfunction, characterised by a reduced nitric oxide (NO) bioavailability due to increased reactive oxygen species (ROS). Sirtuins, and more specifically Sirt-1, are enzymatic proteins involved in regulation of glucose metabolism, inflammation and intracellular levels of ROS. This study aimed to determine the role of Sirt-1 in regulating NO bioavailability of small resistance arteries isolated from subcutaneous tissue of obese patients. 10 subjects (5 with severe obesity, Ob; 5 normal weight controls, Ctrl) underwent biopsy of subcutaneous adipose tissue during laparoscopic bariatric surgery. Function of small arteries was assessed with pressure micromyography. Endothelial-dependent vasodilation (VDep) and NO production was assessed by acetylcholine (ACh, 0,001-100μM), with and without pre-incubation with L-NAME (100μM). The influence of sirtuins on NO bioavailability was assessed repeating Ach with a selective Sirt-1 agonist (SRT-1720, 1μM), alone or plus L-NAME. Ob showed a reduced response to Ach vs Ctrl (P<0.001), associated with a reduced inhibition of L-NAME on Ach (Ob: P=0.002; Ctrl: P<0.001). SRT-1720 improved the VDed induced by Ach (P<0.001) in Ob, although it did not reach values from Ctrl. The simultaneous incubation with L-NAME and SRT-1720 before Ach stimulation abolished the VDed obtained with the incubation of SRT-1720 in the Ob group (SRT-1720 vs SRT-1720+L-NAME: P<0.001). In small arteries of Ob, stimulation of Sirt-1 activity partially restores endothelial function due to an improved NO bioavailability.

scholarly journals The Nitric Oxide System in Peripheral Artery Disease: Connection with Oxidative Stress and Biopterins

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 590
Author(s):  
Ahmed Ismaeel ◽  
Evlampia Papoutsi ◽  
Dimitrios Miserlis ◽  
Ramon Lavado ◽  
Gleb Haynatzki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Peripheral Artery Disease ◽  
Oxide System ◽  
Protein Carbonyls ◽  
Nitric Oxides ◽  
Peripheral Artery ◽  
No Bioavailability ◽  
Artery Disease

Peripheral artery disease (PAD) pathophysiology extends beyond hemodynamics to include other operating mechanisms, including endothelial dysfunction. Oxidative stress may be linked to endothelial dysfunction by reducing nitric oxide (NO) bioavailability. We aimed to investigate whether the NO system and its regulators are altered in the setting of PAD and to assess the relationship between NO bioavailability and oxidative stress. Sera from 35 patients with intermittent claudication (IC), 26 patients with critical limb ischemia (CLI), and 35 non-PAD controls were analyzed to determine levels of tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), nitrate/nitrite (nitric oxides, or NOx), arginine, citrulline, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the oxidative stress markers 8-Oxo-2′-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), advanced glycation end products (AGEs), and protein carbonyls. NOx was significantly lower in IC and CLI patients compared to controls in association with elevated oxidative stress, with the greatest NOx reductions observed in CLI. Compared with controls, IC and CLI patients had reduced BH4, elevated BH2, and a reduced BH4/BH2 ratio. SDMA, the arginine/SDMA ratio, and the arginine/ADMA ratio were significantly higher in CLI patients. The NO system and its regulators are significantly compromised in PAD. This dysregulation appears to be driven by increased oxidative stress and worsens as the disease progresses from claudication to CLI.

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