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

Huang, An; Sun, Dong; Carroll, Mairéad A.; Jiang, Houli; Smith, Carolyn J.; Connetta, Joseph A.; Falck, John R.; Shesely, Edward G.; Koller, Ákos; Kaley, Gabor

doi:10.1152/ajpheart.2001.280.6.h2462

Cited by 114 publications

(131 citation statements)

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“…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). General compensation by combined non-nitric oxide mechanisms is not indicated in the present study, because there is no difference in dilation between control and HHcy arteries with L-NAME (Fig.…”

Section: Discussionmentioning

confidence: 53%

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: 53%

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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“…We reported previously (13,32) that the mechanisms by which endothelial cells release NO in response to changes in shear stress, elicited by changes in perfusate flow, are altered in certain disease states, such as hypertension and heart failure, as indicated specifically by an impaired flow-induced dilation due to a loss of the NOmediated portion of the responses. However, we also found that in skeletal muscle arterioles of transgenic mice in which the gene for eNOS was deleted, endothelial responses to flow/shear stress are preserved via NO-independent signal transduction pathways, resulting in the release of prostaglandins (31) and EDHF (9), to maintain flow-induced dilations in male and female mice, respectively. Although the capacity of coronary vessels to compensate for the loss of NO-mediated dilations to agonists has already been reported (2,7,18), there are no studies extant that have examined the mechanisms by which coronary arteries are responding to shear stress when the gene for eNOS is deleted.…”

mentioning

confidence: 68%

“…Changes in diameter of coronary arteries in response to increases in perfusate flow were studied (9,31). The vessels were equilibrated at 60 mmHg of perfusion pressure for ϳ1 h in a no-flow condition to develop spontaneous tone.…”

Section: Methodsmentioning

confidence: 99%

“…The shear stress-sensitive mechanism is believed to be a potent regulator of coronary vascular tone (29). Shear stress acting on the endothelial lining of blood vessels has been demonstrated to be an important physiological stimulus for the release of endothelial mediators, such as nitric oxide (NO) (28), prostaglandins (15), and endothelium-derived hyperpolarizing factor (EDHF) (9,23), leading to vessel dilation. In the coronary circulation, NO released by endothelial NO synthase (eNOS) is considered to be a primary intrinsic regulatory factor that controls vascular tone in response to changes in shear stress (17,28).…”

mentioning

confidence: 99%

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

Huang

Sun

Shesely

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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106

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. Neuronal NOSdependent dilation to flow in coronary arteries of male eNOS-KO mice. Am J Physiol Heart Circ Physiol 282: H429-H436, 2002; 10.1152/ajpheart.00501.2001.-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 -nitro-L-arginine methyl ester (L-NAME) (10 Ϫ4 M) or indomethacin (10 Ϫ5 M) alone, inhibited flow-induced dilation by ϳ50%, whereas their simultaneous administration abolished the responses. In arteries of eNOS-KO mice, flow-induced dilation was inhibited by ϳ40% with L-NAME. The residual portion (60%) of the response was eliminated by the additional administration of indomethacin. 7-Nitroindazole (10 Ϫ4 M) attenuated flow-induced dilation by ϳ40% 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 ϫ 10 Ϫ5 M) inhibited the L-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, nNOSderived NO, via activation of cGMP, together with prostaglandins, maintains flow-induced dilation in coronary arteries of male eNOS-KO mice. endothelial nitric oxide; prostaglandins; flow-induced dilation ALTHOUGH CARDIAC METABOLISM is a major determinant of coronary perfusion (8), local mechanisms activated by changes in hemodynamic forces, such as changes in blood flow (14, 17) and intravascular pressure (25, 33), also participate significantly in the control of coronary vascular resistance via shear stress and myogenic mechanisms. The shear stress-sensitive mechanism is believed to be a potent regulator of coronary vascular tone (29). Shear stress acting on the endothelial lining of blood vessels has been demonstrated to be an important physiological stimulus for the release of endothelial mediators, such as nitric oxide (NO) (28), prostaglandins (15), and endothelium-derived hyperpolarizing factor (EDHF) (9, 23), leading to vessel dilation. In the coronary circulation, NO released by endothelial NO synthase (eNOS) is considered to be a primary intrinsic regulatory factor that controls vascular tone in response to changes in shear stress (17, 28). We reported previously (13, 32) that the mechanisms by which endothelial cells release NO in response to changes in shear stress, elicited by changes in perfusate flow, are altered in certain disease states, such as hypertension and heart failure, as indicated specifically by an impaired flow-induced dilation due to a loss of the NOmediated portion of the responses. However, we also found that in skeletal muscle arterioles of transgenic mice in which the gene for eNOS ...

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“…78,137 EDHF also assumes the same role in endothelial NO synthase (eNOS) knock-out mice, mediating flow-induced vasodilation of arterioles in SMT. 138 Lastly, it is of interest that kinins have Table 1 Contribution of the disrupted skeletal muscle ACE to the etiology of type 2 diabetes, hypertension and atherosclerosis Key: ACE = angiotensin-converting-enzyme; ADH = antidiuretic hormone; Na+ = NESNS = neuroendocrine sympathetic nervous system; SMC = smooth muscle cell. …”

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

Review: Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis

Dietze¹,

Henriksen

2008

J Renin Angiotensin Aldosterone Syst

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Recent evidence suggests a coordinated regulation by the local renin-angiotensin system (RAS) and tissue kallikrein-kinin system (TKKS) of blood flow and substrate supply in oxidative red myofibres of skeletal muscle tissue during endurance exercise.The performance of these myofibres is dependent on the increased oxidation of substrates facilitated by augmenting nutritive blood flow and glucose uptake. Humoral factors released by the contracting fibres, such as adenosine and kinins, are suggested to be responsible for this metabolic adjustment.The considerable drain of blood volume and the enormous consumption of glucose during endurance exercise require a control mechanism for the maintenance of blood pressure (BP) and glucose homeostasis. This is achieved by the sympathetic nervous system and its subordinate RAS, which is located in the nutritive vessels and parenchyma of the red myofibres. The angiotensin-converting enzyme (ACE) is the primary enzyme responsible for kinin degradation during exercise, underscoring the important interrelationship between the RAS and the TKKS in the critical role of kinins in the multifactorial regulation of muscle bioenergetics and glucose and BP homeostasis. Importantly, overactivity of the ACE, as occurs in individuals displaying risk factors such as overweight, causes exaggerated BP response and reduced glucose disposal. If they persist over years, compensatory responses to this ACE overactivity, such as hypersecretion of insulin and compliance of the vessel walls, will inevitably be exhausted, leading ultimately to the manifestation of type 2 diabetes and hypertension. This concept also provides a unifying explanation for the beneficial effects of ACE-inhibitors and Angiotensin II receptor antagonists in the treatment of hypertension and insulin resistance.Need for control of blood pressure and glucose homeostasis during endurance exercise performance The regulation of muscle bioenergetics during exercise has been studied for more than 100 years.

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

Cited by 114 publications

References 35 publications

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

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

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

Review: Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis

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