Acetylcholine‐induced relaxation of peripheral arteries isolated from mice lacking endothelial nitric oxide synthase

Waldron, Gareth; Ding, Hong; Lovren, Fina; Kubes, Paul; Triggle, Chris R.

doi:10.1038/sj.bjp.0702858

Cited by 116 publications

(103 citation statements)

References 21 publications

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“…The mesenteric arteries used in the present study rely on both nitric oxide and EDHF for agonist-induced endotheliumdependent dilation (12,15,30). Studies in which nitric oxide has been blocked pharmacologically or by genetic knockout of eNOS have shown a general compensation for the loss of nitric oxide by upregulation of EDHF or prostacyclin (4,6,16,27).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, disease in resistance vessels, in addition to conduit arteries, is a feature of HHcy (18). This artery dilates to agonists through roughly equal contribution from nitric oxide and non-nitric oxide mechanisms (30). Thus, it provides a model for examining the correlation between nitric oxidedependent function and eNOS expression and regulation, and the relative contribution of the various mechanisms of endothelium-dependent dilation with HHcy.…”

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confidence: 99%

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Chronic diet-induced hyperhomocysteinemia impairs eNOS regulation in mouse mesenteric arteries

Looft‐Wilson¹,

Ashley²,

Billig³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Looft-Wilson RC, Ashley BS, Billig JE, Wolfert MR, Ambrecht LA, Bearden SE. Chronic diet-induced hyperhomocysteinemia impairs eNOS regulation in mouse mesenteric arteries. Am J Physiol Regul Integr Comp Physiol 295: R59 -R66, 2008. First published April 30, 2008 doi:10.1152/ajpregu.00833.2007.-Hyperhomocysteinemia (HHcy) impairs endothelium-dependent vasodilation by increasing reactive oxygen species, thereby reducing nitric oxide (NO ⅐ ) bioavailability. It is unclear whether reduced expression or function of the enzyme that produces NO ⅐ , endothelial nitric oxide synthase (eNOS), also contributes. It is also unclear whether resistance vessels that utilize both NO ⅐ and non-NO ⅐ vasodilatory mechanisms, undergo alteration of non-NO ⅐ mechanisms in this condition. We tested these hypotheses in male C57BL/6 mice with chronic HHcy induced by 6-wk high methionine/low-B vitamin feeding (Hcy: 89.2 Ϯ 49.0 M) compared with age-matched controls (Hcy: 6.6 Ϯ 1.9 M), using first-order mesenteric arteries. Dilation to ACh (10 Ϫ9 -10 Ϫ4 M) was measured in isolated, cannulated, and pressurized (75 mmHg) arteries with and without N G -nitro-L-arginine methyl ester (L-NAME) (10 Ϫ4 M) and/or indomethacin (10 Ϫ5 M) to test endothelium-dependent dilation and non-NO ⅐ -dependent dilation, respectively. The time course of dilation to ACh (10 Ϫ4 M) was examined to compare the initial transient dilation due to non-NO ⅐ , non-prostacyclin mechanism and the sustained dilation due to NO ⅐ . These experiments indicated that endothelium-dependent dilation was attenuated (P Ͻ 0.05) in HHcy arteries due to downregulation of only NO ⅐ -dependent dilation. Western blot analysis indicated significantly less (P Ͻ 0.05) basal eNOS and phospho-S1179-eNOS/eNOS in mesenteric arteries from HHcy mice but no difference in phospho-T495-eNOS/eNOS. S1179 eNOS phosphorylation was also significantly less in these arteries when stimulated with ACh ex vivo or in situ. Real-time PCR indicated no difference in eNOS mRNA levels. In conclusion, chronic dietinduced HHcy in mice impairs eNOS protein expression and phosphorylation at S1179, coincident with impaired NO ⅐ -dependent dilation, which implicates dysfunction in eNOS post-transcriptional regulation in the impaired endothelium-dependent vasodilation and microvascular disease that is common with HHcy.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Chronic diet-induced hyperhomocysteinemia impairs eNOS regulation in mouse mesenteric arteries

Looft‐Wilson¹,

Ashley²,

Billig³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Mice lacking eNOS exhibit endothelial dysfunction, 25 whereas statins have been shown to upregulate eNOS. 15 However, effects of maternal protein restriction on eNOS activity or expression are not supported by the current data, which indicates no change in either hepatic eNOS activity or vascular mRNA levels between the groups, a finding that is in contrast to previous findings.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Restores Endothelial Function in Offspring of Protein-Restricted Rats in a Cholesterol-Independent Manner

et al. 2009

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Abstract-Maternal protein restriction in rats leads to endothelial dysfunction and decreased NO bioavailability in the offspring. Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) are recognized to have pleiotropic actions including increasing NO bioavailability and reducing inflammation and oxidative damage. This study assessed statin treatment on vascular function in a model of endothelial dysfunction, which is independent of dyslipidemia. Wistar rats were fed a control (18% casein) or protein-restricted (9% casein) diet throughout pregnancy. At weaning, a subset of the protein-restricted group was given atorvastatin (10 mg/kg per day) in the drinking water. At 145 days of age, offspring were euthanized by CO 2 inhalation. Plasma samples were collected for markers of inflammation, vascular reactivity of the thoracic aorta, and small mesenteric arteries were assessed on the wire myograph, and tissues were snap frozen for molecular biology analysis. Thoracic aorta endothelial-dependent vasodilatation was attenuated in the male offspring from both protein-restricted groups compared with controls (PϽ0.05) but was similar in females (P value not significant). Endothelial-dependent dilatation of mesenteric arteries was attenuated in male and female protein-restricted offspring (PϽ0.05) and was corrected by atorvastatin. Maternal protein restriction increased plasma inflammatory markers granulocyte chemotactic protein, lipocalin-2, and ␤ 2 -microglobulin in male and C-reactive protein in female offspring (PϽ0.05). Atorvastatin had no effect on inflammatory markers in the males but restored C-reactive protein to control levels in the females (PϽ0.05). Aortic and mesenteric artery mRNA levels of endothelial NO synthase, superoxide dismutase 1, and tumor necrosis factor-␣ were unchanged. These data suggest that atorvastatin can restore endothelial function in this model, but its effects are gender specific and dependent on the vascular bed. Key Words: statins (atorvastatin) Ⅲ experimental models Ⅲ fetal programming Ⅲ vascular biology Ⅲ endothelium Ⅲ nitric oxide Ⅲ inflammation T here is considerable evidence that the etiology of cardiovascular and metabolic diseases has origins partly in the developmental environment. 1 A widely used animal model to study this phenomenon is the rat, in which the restriction of dietary protein during pregnancy leads to raised blood pressure and endothelial dysfunction in the offspring. [2][3][4] Increasingly, evidence from this model points to a disruption to the NO pathway as a key component of the underlying pathophysiology. 4,5 The healthy vascular endothelium plays an important role in maintaining vascular tone through the release of factors including NO, prostacyclin, and endothelial-derived hyperpolarizing factor. 6 The importance of a healthy endothelium is seen in cardiovascular and metabolic diseases, where endothelial dysfunction is associated with atherosclerosis, hypertension, and the metabolic syndrome. 7-9 Important in the development of such endothelial ...

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“…Cardiovascular diseases, such as arteriosclerosis and SAH, may be related to increase of vascular tonus derived from disorders in endothelial relaxation (29) . The natural aging process can also induce to alterations in the vascular endothelium (30) .…”

Section: Discussionmentioning

confidence: 99%

“…At basal conditions, the vascular endothelium secretes relaxing factors (nitric oxide, NO; prostacyclins) and contractile factors (endoperoxides, thromboxane A 2 and endothelins, ET) (29) . The increase of contraction strength of the arteries as well as the insufficiency in the endothelial relaxation are related to decrease of NO availability in the vascular endothelium (14,15) .…”

Section: Concerningmentioning

confidence: 99%

Impacto da desnutrição e do treinamento aeróbico moderado sobre a estrutura da parede arterial de ratos em processo de envelhecimento

Brito

Maux²,

Oliveira³

et al. 2011

Rev Bras Med Esporte

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We evaluated the late effects of multi-needy malnutrition imposed during lactation and the possible effects and / or changes to both the aging process as of moderate aerobic training on the luminal diameter and the tunica media area of the left common carotid artery, horizontal aorta and thoracic aorta of rats in the aging process. Twenty-four Wistar male rats were separated according to diet and physical training: SNG -Sedentary Nourished Group, TNG -Trained Nourished Group, SMG-Sedentary Malnourished Group and TMG -Trained Malnourished Group. At 10 months, the TNG and TMG were submitted to aerobic training in water for 8 weeks. Then the mice were anesthetized and sacrificed and the arterial fragments were collected for histological processing. The area of the tunica media was measured by the difference between external and internal areas of the arterial wall and luminal diameter was measured from the average of two diameters measured from four points marked on the internallayer of the vessel. The area of tunica media decreased in the horizontal aorta when compared groups SNG x SMG (p = 0.015) and increased in left common carotid artery between groups SNG and TNG (p = <0.001). The thoracic aorta showed an increase in luminal diameter when comparing the SMG with the TMG (p = 0.041). Multi-needy malnutrition induced both to partial changes in the horizontal aorta wall, as well as physical training was able to promote changes in the tunica media area of the left common carotid artery and luminal diameter of the thoracic aorta.

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Acetylcholine‐induced relaxation of peripheral arteries isolated from mice lacking endothelial nitric oxide synthase

Cited by 116 publications

References 21 publications

Chronic diet-induced hyperhomocysteinemia impairs eNOS regulation in mouse mesenteric arteries

Chronic diet-induced hyperhomocysteinemia impairs eNOS regulation in mouse mesenteric arteries

Atorvastatin Restores Endothelial Function in Offspring of Protein-Restricted Rats in a Cholesterol-Independent Manner

Impacto da desnutrição e do treinamento aeróbico moderado sobre a estrutura da parede arterial de ratos em processo de envelhecimento

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