Neuronal NOS-dependent dilation to flow in coronary arteries of male eNOS-KO mice

2002 ◽  
Vol 282 (2) ◽  
pp. H429-H436 ◽  
Author(s):  
An Huang ◽  
Dong Sun ◽  
Edward G. Shesely ◽  
Ellen M. Levee ◽  
Akos Koller ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Coronary Arteries ◽  
No Synthase ◽  
Simultaneous Administration ◽  
Wild Type ◽  
Basal Tone ◽  
Neuronal Nos ◽  
Immunohistochemical Evidence ◽  
Endothelial Nitric Oxide ◽  
Arterial Endothelium

Flow-induced dilation was examined in isolated coronary arteries of endothelial nitric oxide (NO) synthase knockout mice (eNOS-KO) and wild-type (WT) mice. The basal tone of arteries (percentage of passive diameter) was significantly greater in eNOS-KO than in WT mice; their flow-induced dilations, however, were similar. Endothelial removal eliminated the dilations in vessels of both strains of mice. In arteries of WT mice, N ω-nitro-l-arginine methyl ester (l-NAME) (10−4 M) or indomethacin (10−5 M) alone, inhibited flow-induced dilation by ∼50%, whereas their simultaneous administration abolished the responses. In arteries of eNOS-KO mice, flow-induced dilation was inhibited by ∼40% with l-NAME. The residual portion (60%) of the response was eliminated by the additional administration of indomethacin. 7-Nitroindazole (10−4 M) attenuated flow-induced dilation by ∼40% in arteries of eNOS-KO mice, but did not affect responses in those of WT mice. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (3 × 10−5 M) inhibited thel-NAME/7-nitroindazole-sensitive portion of the responses in arteries of eNOS-KO mice. Immunohistochemical evidence confirms the presence of neuronal NOS (nNOS) in the arterial endothelium of eNOS-KO mice. In conclusion, nNOS-derived NO, via activation of cGMP, together with prostaglandins, maintains flow-induced dilation in coronary arteries of male eNOS-KO mice.

scholarly journals Acetylcholine causes endothelium-dependent contraction of mouse arteries

2005 ◽  
Vol 289 (3) ◽  
pp. H1027-H1032 ◽  
Author(s):  
Yingbi Zhou ◽  
Saradhadevi Varadharaj ◽  
Xue Zhao ◽  
Narasimham Parinandi ◽  
Nicholas A. Flavahan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Isometric Tension ◽  
No Synthase ◽  
Cyclooxygenase Inhibitor ◽  
Wild Type ◽  
Endothelial Denudation ◽  
Prostaglandin H ◽  
Endothelial Nitric Oxide ◽  
Endothelium Dependent Relaxation

The goal of this study was to determine whether acetylcholine evokes endothelium-dependent contraction in mouse arteries and to define the mechanisms involved in regulating this response. Arterial rings isolated from wild-type (WT) and endothelial nitric oxide (NO) synthase knockout (eNOS−/−) mice were suspended for isometric tension recording. In abdominal aorta from WT mice contracted with phenylephrine, acetylcholine caused a relaxation that reversed at the concentration of 0.3–3 μM. After inhibition of NO synthase [with Nω-nitro-l-arginine methyl ester (l-NAME), 1 mM], acetylcholine (0.1–10 μM) caused contraction under basal conditions or during constriction to phenylephrine, which was abolished by endothelial denudation. This contraction was inhibited by the cyclooxygenase inhibitor indomethacin (1 μM) or by a thromboxane A2 (TxA2) and/or prostaglandin H2 receptor antagonist SQ-29548 (1 μM) and was associated with endothelium-dependent generation of the TxA2 metabolite TxB2. Also, SQ-29548 (1 μM) abolished the reversal in relaxation evoked by 0.3–3 μM acetylcholine and subsequently enhanced the relaxation to the agonist. The magnitude of the endothelium-dependent contraction to acetylcholine (0.1–10 μM) was similar in aortas from WT mice treated in vitro with l-NAME and from eNOS−/− mice. In addition, we found that acetylcholine (10 μM) also caused endothelium-dependent contraction in carotid and femoral arteries of eNOS−/− mice. These results suggest that acetylcholine initiates two competing responses in mouse arteries: endothelium-dependent relaxation mediated predominantly by NO and endothelium-dependent contraction mediated most likely by TxA2.

scholarly journals Vasodilator mechanisms in the coronary circulation of endothelial nitric oxide synthase-deficient mice

2000 ◽  
Vol 279 (4) ◽  
pp. H1906-H1912 ◽  
Author(s):  
Kathryn G. Lamping ◽  
Daniel W. Nuno ◽  
Edward G. Shesely ◽  
Nobuyo Maeda ◽  
Frank M. Faraci
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Coronary Arteries ◽  
Endothelial Nitric Oxide Synthase ◽  
Coronary Circulation ◽  
Wild Type ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Endothelium Dependent Relaxation ◽  
Deficient Mice

Previous studies have demonstrated that responses to endothelium-dependent vasodilators are absent in the aortas from mice deficient in expression of endothelial nitric oxide synthase (eNOS −/− mice), whereas responses in the cerebral microcirculation are preserved. We tested the hypothesis that in the absence of eNOS, other vasodilator pathways compensate to preserve endothelium-dependent relaxation in the coronary circulation. Diameters of isolated, pressurized coronary arteries from eNOS −/−, eNOS heterozygous (+/−), and wild-type mice (eNOS +/+ and C57BL/6J) were measured by video microscopy. ACh (an endothelium-dependent agonist) produced vasodilation in wild-type mice. This response was normal in eNOS +/− mice and was largely preserved in eNOS −/− mice. Responses to nitroprusside were also similar in arteries from eNOS +/+, eNOS +/−, and eNOS −/− mice. Dilation to ACh was inhibited by N G-nitro-l-arginine, an inhibitor of NOS in control and eNOS −/− mice. In contrast, trifluoromethylphenylimidazole, an inhibitor of neuronal NOS (nNOS), decreased ACh-induced dilation in arteries from eNOS-deficient mice but had no effect on responses in wild-type mice. Indomethacin, an inhibitor of cyclooxygenase, decreased vasodilation to ACh in eNOS-deficient, but not wild-type, mice. Thus, in the absence of eNOS, dilation of coronary arteries to ACh is preserved by other vasodilator mechanisms.

Neuregulin-1 Compensates for Endothelial Nitric Oxide Synthase Deficiency

2021 ◽  
Author(s):  
Hadis Shakeri ◽  
Jente R.A. Boen ◽  
Sofie De Moudt ◽  
Jhana O. Hendrickx ◽  
Arthur J.A. Leloup ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Fibrosis ◽  
Separate Experiment ◽  
No Production ◽  
Ang Ii ◽  
Wild Type ◽  
Paracrine Factor ◽  
Renal Hypertrophy ◽  
Neuregulin 1 ◽  
Endothelial Nitric Oxide

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. Methods. We characterized eNOS null and wild type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, 8 groups of mice were divided into 4 groups of eNOS null mice and wild type (WT) mice; half of the mice received angiotensin II (Ang II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. Results. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, Ang II administration increased cardiac fibrosis, but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented the cardiac and renal hypertrophy and fibrosis caused by Ang II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. Conclusion. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.

Abstract WP103: Endothelial Nitric Oxide Synthase Regulates White Matter Changes after Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Xu Cui ◽  
Michael Chopp ◽  
Tao Yan ◽  
Ruizhuo Ning ◽  
Cynthia Roberts ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
White Matter ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Wild Type ◽  
White Matter Damage ◽  
White Matter Changes ◽  
Significant Difference ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Background: Stroke induced white matter damage is associated with neurological functional deficits, but the underlying mechanisms are not well understood. Endothelial nitric oxide synthase knockout (eNOS-/-) mice exhibited a higher mortality, more severe neurological functional deficit, and decreased neurogenesis, angiogenesis and arteriogenesis after stroke than wild type mice. There are no reports as to whether eNOS is related to the white matter change post-stroke. Methods: Adult male C57BL/6 WT and eNOS -/- mice were subjected to permanent middle cerebral artery occlusion (MCAo) by a filament and sacrificed 7 days after MCAo. Functional evaluation, infarct volume measurement, and immunostaining for analysis of white matter changes were performed. Results: There is no significant difference in the infarction volume between wild type and eNOS -/- (wild type : 23.09%±3.32%; eNOS-/-: 27.83%±4.92%, p=0.436, n=9/group). However, eNOS -/- mice showed significantly decreased functional outcome tested by the singal pellet reaching test (wild type: 38.46%%±1.43%, eNOS-/-: 27.45%±2.41%, p=0.0017). eNOS -/- mice also exhibited increased white matter damage compared to wild type mice, including decrease: 1. Axonal density stained by Bielshowsky Silver in the ipsilateral striatal bundles (wild type: 22.06%±3.0%, eNOS-/-: 13.32%±2.18%,, p=0.031), and in the contralateral striatal bundles (wild type: 65.35%±3.97%, eNOS-/-: 29.38%±5.84%, p=0.02); 2. Density of phasphorylated neurofilament by SMI31-immunoflureoscent staining (wild type: 24.11%±2.06%, eNOS-/-: 7.90%±1.70%, p=0.009); 3. The number of CNPase-positive oligodendrocytes in the ischemic border (wild type: 52.23±5.10, eNOS-/-: 35.59±5.33, p=0.041); 4. The number of NG2-positive oligodendrocyte progenitors in the ischemic border (wild type: 26.22±2.31, eNOS-/-: 18.38±1.95, p=0.0187). There is no significant difference in the density of Luxol fast blue stained myelin in the ipsilateral striatal bundles between wild type and eNOS -/- mice (wild type: 25.21%±3.64%; eNOS-/-: 21.39%±6.29%, p=0.260). Conclusions: We are the first to report that eNOS not only regulates vascular changes and neurogenesis, but also plays an important role in white matter changes after stroke.

Recombinant Gene Transfer of Endothelial Nitric Oxide Synthase Augments Coronary Artery Relaxations During Hypoxia

Circulation ◽  
1999 ◽  
Vol 100 (suppl_2) ◽  
Author(s):  
David G. Cable ◽  
Vincent J. Pompili ◽  
Timothy O’Brien ◽  
Hartzell V. Schaff
Keyword(s):  
Nitric Oxide ◽  
Coronary Artery ◽  
Nitric Oxide Synthase ◽  
Gene Transfer ◽  
Coronary Arteries ◽  
Endothelial Nitric Oxide Synthase ◽  
No Production ◽  
Viral Control ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Background —Coronary arteries respond to hypoxia with transient relaxations, which increases coronary blood flow, in part, by release of nitric oxide. We hypothesized that increased expression of nitric oxide synthase might further augment blood vessel relaxation during hypoxia. The present study examined the effect of adenovirus-mediated transfer of bovine endothelial nitric oxide synthase (eNOS) on hypoxia-induced transient relaxations in canine coronary arteries. Methods and Results —Paired segments of coronary arteries were exposed to vehicle (phosphate-buffered saline with albumin) or an adenovirus encoding either E coli β-galactosidase (Ad.CMVLacZ, viral control; 10 10 pfu/mL) or eNOS (Ad.CMVeNOS; 10 10 pfu/mL) for 2 hours at 37°C. Immunohistochemistry with a monoclonal antibody specific for eNOS documented both endothelial and adventitial expression in Ad.CMVeNOS arteries, whereas vehicle and viral controls demonstrated only constitutive expression. Levels of cGMP were increased 5-fold in Ad.CMVeNOS arteries compared with controls. In arteries exposed to Ad.CMVeNOS, maximum contraction to prostaglandin F 2α was reduced compared with viral controls, and this effect was eliminated by pretreatment with a competitive inhibitor of eNOS ( N G -monomethyl- l -arginine, 10 −3 mol/L). Hypoxia-induced transient relaxation (95% N 2 -5% CO 2 ) in Ad.CMVeNOS arteries (45.2±8.8%, n=6) was augmented compared with vehicle (26.3±6.0%) or viral (27.2±7.1%) controls. Conclusions —Adenovirus-mediated gene transfer of nitric oxide synthase reduces receptor-dependent contractions and augments hypoxia-induced relaxations in canine coronary arteries; this method of augmentation of NO production might be advantageous for reduction of coronary artery vasospasm.

Calcium regulates estrogen increase in permeability of cultured CaSki epithelium by eNOS-dependent mechanism

2000 ◽  
Vol 279 (5) ◽  
pp. C1495-C1505 ◽  
Author(s):  
George I. Gorodeski
Keyword(s):  
Nitric Oxide ◽  
Endothelial Nitric Oxide Synthase ◽  
Cytosolic Calcium ◽  
No Synthase ◽  
Calcium Dependent ◽  
Steady State Levels ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Dependent Mechanism

Estrogen increases baseline transepithelial permeability across CaSki cultures and augments the increase in permeability in response to hypertonic gradients. In estrogen-treated cells, lowering cytosolic calcium abrogated the hypertonicity-induced augmented increase in permeability and decreased baseline permeability to a greater degree than in estrogen-deprived cells. Steady-state levels of cytosolic calcium in estrogen-deprived cells were higher than in estrogen-treated cells. Increases in extracellular calcium increased cytosolic calcium more in estrogen-deprived cells than in estrogen-treated cells. However, in estrogen-treated cells, increasing cytosolic calcium was associated with greater increases in permeability in response to hypertonic gradients than in estrogen-deprived cells. Lowering cytosolic calcium blocked the estrogen-induced increase in nitric oxide (NO) release and in the in vitro conversion of l-[3H]arginine to l-[3H]citrulline. Treatment with estrogen upregulated mRNA of the NO synthase isoform endothelial nitric oxide synthase (eNOS). These results indicate that cytosolic calcium mediates the responses to estrogen and suggest that the estrogen increase in permeability and the augmented increase in permeability in response to hypertonicity involve an increase in NO synthesis by upregulation of the calcium-dependent eNOS.

EDHF mediates flow-induced dilation in skeletal muscle arterioles of female eNOS-KO mice

2001 ◽  
Vol 280 (6) ◽  
pp. H2462-H2469 ◽  
Author(s):  
An Huang ◽  
Dong Sun ◽  
Mairead A. Carroll ◽  
Houli Jiang ◽  
Carolyn J. Smith ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Endothelial Nitric Oxide Synthase ◽  
Hexanoic Acid ◽  
Gracilis Muscle ◽  
Wild Type ◽  
Basal Release ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Cytochrome P 450

Vasodilation to increases in flow was studied in isolated gracilis muscle arterioles of female endothelial nitric oxide synthase (eNOS)-knockout (KO) and female wild-type (WT) mice. Dilation to flow (0–10 μl/min) was similar in the two groups, yet calculated wall shear stress was significantly greater in arterioles of eNOS-KO than in arterioles of WT mice. Indomethacin, which inhibited flow-induced dilation in vessels of WT mice by ∼40%, did not affect the responses of eNOS-KO mice, whereas miconazole and 6-(2-proparglyoxyphenyl)hexanoic acid (PPOH) abolished the responses. Basal release of epoxyeicosatrienonic acids from arterioles was inhibited by PPOH. Iberiotoxin eliminated flow-induced dilation in arterioles of eNOS-KO mice but had no effect on arterioles of WT mice. In WT mice, neither N ω-nitro-l-arginine methyl ester nor miconazole alone affected flow-induced dilation. Combination of both inhibitors inhibited the responses by ∼50%. 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ) alone inhibited flow-induced dilation by ∼49%. ODQ + indomethacin eliminated the responses. Thus, in arterioles of female WT mice, nitric oxide and prostaglandins mediate flow-induced dilation. When eNOS is inhibited, endothelium-derived hyperpolarizing factor substitutes for nitric oxide. In female eNOS-KO mice, metabolites of cytochrome P-450, via activation of large-conductance Ca2+-activated K+ channels of smooth muscle, mediate entirely the arteriolar dilation to flow.

Regulation of endothelial nitric oxide synthase mRNA, protein, and activity during cell growth

1994 ◽  
Vol 267 (5) ◽  
pp. C1381-C1388 ◽  
Author(s):  
J. F. Arnal ◽  
J. Yamin ◽  
S. Dockery ◽  
D. G. Harrison
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Cell Growth ◽  
Endothelial Nitric Oxide Synthase ◽  
Northern Blot Analysis ◽  
No Synthase ◽  
Proliferating Cells ◽  
Bovine Endothelial Cells ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Cell growth influences the expression of several important tissue-specific functions. We sought to examine the effect of cell proliferation on nitric oxide (NO) synthase gene expression in cultured aortic bovine endothelial cells. Western and Northern blot analysis revealed three- and sixfold increases in NO synthase protein and mRNA, respectively, in growing compared with growth-arrested cells. The release of nitrogen oxides was also increased in proliferating cells compared with growth-arrested cells, as was the NO synthase activity assessed by L-arginine/L-citrulline conversion. Neither NO synthase inhibitors nor superoxide dismutase affected proliferation or thymidine incorporation, suggesting that increased NO release had no effect on endothelial cell growth. In conclusion, these studies demonstrate that expression of endothelial cell NO synthase is markedly increased in proliferating compared with quiescent nongrowing cells. The mechanisms underlying this and its physiological consequences remain to be defined.

scholarly journals Hematopoietic Cell–Expressed Endothelial Nitric Oxide Protects the Liver From Insulin Resistance

2020 ◽  
Vol 40 (3) ◽  
pp. 670-681
Author(s):  
Brian P. Dick ◽  
Ryan McMahan ◽  
Taft Knowles ◽  
Lev Becker ◽  
Sina A. Gharib ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Bone Marrow ◽  
Inflammatory Responses ◽  
Hepatic Insulin Resistance ◽  
Metabolic Homeostasis ◽  
Wild Type ◽  
Bone Marrow Derived Cells ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Objective: Mice genetically deficient in endothelial nitric oxide synthase (Nos3 −/− ) have fasting hyperinsulinemia and hepatic insulin resistance, indicating the importance of Nos3 (nitric oxide synthase) in maintaining metabolic homeostasis. Although the current paradigm holds that these metabolic effects are derived specifically from the expression of Nos3 in the endothelium, it has been established that bone marrow–derived cells also express Nos3. The aim of this study was to investigate whether bone marrow–derived cell Nos3 is important in maintaining metabolic homeostasis. Approach and Results: To test the hypothesis that bone marrow–derived cell Nos3 contributes to metabolic homeostasis, we generated chimeric male mice deficient or competent for Nos3 expression in circulating blood cells. These mice were placed on a low-fat diet for 5 weeks, a time period which is known to induce hepatic insulin resistance in global Nos3-deficient mice but not in wild-type C57Bl/6 mice. Surprisingly, we found that the absence of Nos3 in the bone marrow–derived component is associated with hepatic insulin resistance and that restoration of Nos3 in the bone marrow–derived component in global Nos3-deficient mice is sufficient to restore hepatic insulin sensitivity. Furthermore, we found that overexpression of Nos3 in bone marrow–derived component in wild-type mice attenuates the development of hepatic insulin resistance during high-fat feeding. Finally, compared with wild-type macrophages, the loss of macrophage Nos3 is associated with increased inflammatory responses to lipopolysaccharides and reduced anti-inflammatory responses to IL-4, a macrophage phenotype associated with the development of hepatic and systemic insulin resistance. Conclusions: These results would suggest that the metabolic and hepatic consequences of high-fat feeding are mediated by loss of Nos3/nitric oxide actions in bone marrow–derived cells, not in endothelial cells.

Sign in / Sign up

Export Citation Format

Share Document