Enhanced K+-channel-mediated endothelium-dependent local and conducted dilation of small mesenteric arteries from ApoE−/− mice

Beleznai, Timea; Takano, Haruo; Hamill, Claire; Yarova, Polina; Douglas, Gillian; Channon, Keith M.; Dora, K A

doi:10.1093/cvr/cvr181

Cited by 23 publications

(39 citation statements)

References 36 publications

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“…In the latter study and in 16-week-old Apoe 2/2 mice on HFD in the present work, decreased EDR was accompanied by a diminished endotheliumindependent vasorelaxation in response to an NO donor, suggesting that there is a decreased NO relaxant response of VSMC in Apoe 2/2 mice. In other studies, however, no modification of ACh-induced EDR in mesenteric arteries was observed in 10-to 16-week old Apoe 2/2 mice (Morikawa et al, 2005;Beleznai et al, 2011). It is important to point out that our study design differed from these other studies.…”

Section: Discussionmentioning

confidence: 63%

“…Whereas some groups have reported similar findings (Andrews et al, 2009;Hosoya et al, 2010), others have shown that in mesenteric arteries from WT (Morikawa et al, 2005;Ohashi et al, 2012) and Apoe 2/2 mice (Beleznai et al, 2011), EDR to ACh is resistant to eNOS inhibition. Such discrepancies could be explained by different housing conditions, intestinal microbiota differences, or technical aspects of myography.…”

Section: Discussionmentioning

confidence: 77%

“…It is important to point out that our study design differed from these other studies. For example, we used NE to precontract vessels, whereas Morikawa et al (2005) used prostaglandin F2a, andBeleznai et al (2011) and Ding et al (2005) used phenylephrine. Dysfunction in a 2 -adrenoceptor-mediated EDR has been reported in Apoe 2/2 mice (Lee et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In resistance arteries, decreased NO-mediated EDR may be substituted by an EDH mechanism (Beleznai et al, 2011). Although it is known that ET-1 impairs EDR, a specific role of ET-1 on EDR signaling pathways during the development of atherosclerosis is unknown.…”

Section: /2mentioning

confidence: 99%

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Preservation of Endothelium-Dependent Relaxation in Atherosclerotic Mice with Endothelium-Restricted Endothelin-1 Overexpression

Mian

Idris-Khodja

et al. 2013

J Pharmacol Exp Ther

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In human atherosclerosis, which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ET A receptor antagonists improve coronary endothelial function. Mice overexpressing ET-1 specifically in the endothelium (eET-1) crossed with atherosclerosis-prone apolipoprotein E knockout mice (Apoe 2/2 ) exhibit exaggerated high-fat diet (HFD)-induced atherosclerosis. Since endothelial dysfunction often precedes atherosclerosis development, we hypothesized that mice overexpressing endothelial ET-1 on a genetic background deficient in apolipoprotein E (eET-1/Apoe 2/2 ) would have severe endothelial dysfunction. To test this hypothesis, we investigated endothelium-dependent relaxation (EDR) to acetylcholine in eET-1/Apoe 2/2 mice. EDR in mesenteric resistance arteries from 8-and 16-week-old mice fed a normal diet or HFD was improved in eET-1/Apoe 2/2 compared with Apoe 2/2 mice. Nitric oxide synthase (NOS) inhibition abolished EDR in Apoe 2/2 . EDR in eET-1/Apoe 2/2 mice was resistant to NOS inhibition irrespective of age or diet. Inhibition of cyclooxygenase, the cytochrome P450 pathway, and endothelium-dependent hyperpolarization (EDH) resulted in little or no inhibition of EDR in eET-1/Apoe 2/2 compared with wild-type (WT) mice. In eET-1/Apoe 2/2 mice, blocking of EDH or soluble guanylate cyclase (sGC), in addition to NOS inhibition, decreased EDR by 36 and 30%, respectively. The activation of 4-aminopyridine-sensitive voltage-dependent potassium channels (K v ) during EDR was increased in eET-1/Apoe 2/2 compared with WT mice. We conclude that increasing eET-1 in mice that develop atherosclerosis results in decreased mutual dependence of endothelial signaling pathways responsible for EDR, and that NOS-independent activation of sGC and increased activation of K v are responsible for enhanced EDR in this model of atherosclerosis associated with elevated endothelial and circulating ET-1.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: /2mentioning

confidence: 99%

See 2 more Smart Citations

Preservation of Endothelium-Dependent Relaxation in Atherosclerotic Mice with Endothelium-Restricted Endothelin-1 Overexpression

Mian

Idris-Khodja

et al. 2013

J Pharmacol Exp Ther

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“…Along with the lesion progression in size and composition, the endothelium is severely damaged with increased leakage, loss of tight junctions of endothelial cells and increased repair, while a decrease in endothelial progenitor cells that are involved in vascular repair is observed [69, 70]. At 13 months of age, ApoE -/- mice exhibit a 61% occlusion of the lumen and decreased endothelial-dependent relaxation to acetylcholine, an increase in stiffness of conduit arteries leading to elastic laminar fragmentation, while endothelium independent relaxation remains intact [68, 71–74]. In contrast to humans, the impairment in endothelium dependent vasodilation in ApoE -/- mice appears to be focal rather than systemic [47, 75].…”

Section: Manifestations Of Apoe Deficiency In the Cardiovascular Systemmentioning

confidence: 99%

Crossroads between peripheral atherosclerosis, western-type diet and skeletal muscle pathophysiology: emphasis on apolipoprotein E deficiency and peripheral arterial disease

Sfyri

Matsakas

2017

J Biomed Sci

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Atherosclerosis is a chronic inflammatory process that, in the presence of hyperlipidaemia, promotes the formation of atheromatous plaques in large vessels of the cardiovascular system. It also affects peripheral arteries with major implications for a number of other non-vascular tissues such as the skeletal muscle, the liver and the kidney. The aim of this review is to critically discuss and assimilate current knowledge on the impact of peripheral atherosclerosis and its implications on skeletal muscle homeostasis. Accumulating data suggests that manifestations of peripheral atherosclerosis in skeletal muscle originates in a combination of increased i)-oxidative stress, ii)-inflammation, iii)-mitochondrial deficits, iv)-altered myofibre morphology and fibrosis, v)-chronic ischemia followed by impaired oxygen supply, vi)-reduced capillary density, vii)- proteolysis and viii)-apoptosis. These structural, biochemical and pathophysiological alterations impact on skeletal muscle metabolic and physiologic homeostasis and its capacity to generate force, which further affects the individual’s quality of life. Particular emphasis is given on two major areas representing basic and applied science respectively: a)-the abundant evidence from a well-recognised atherogenic model; the Apolipoprotein E deficient mouse and the role of a western-type diet and b)-on skeletal myopathy and oxidative stress-induced myofibre damage from human studies on peripheral arterial disease. A significant source of reactive oxygen species production and oxidative stress in cardiovascular disease is the family of NADPH oxidases that contribute to several pathologies. Finally, strategies targeting NADPH oxidases in skeletal muscle in an attempt to attenuate cellular oxidative stress are highlighted, providing a better understanding of the crossroads between peripheral atherosclerosis and skeletal muscle pathophysiology.

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Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Tykocki

Boerman

Jackson

2017

Comprehensive Physiology

258

343

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Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body’s tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes.

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Enhanced K+-channel-mediated endothelium-dependent local and conducted dilation of small mesenteric arteries from ApoE−/− mice

Abstract: In small mesenteric arteries of ApoE(-/-) mice, NO-independent dilation is enhanced. Since both NO-dependent and -independent pathways can stimulate local and conducted dilation, the potential for reducing vascular resistance is improved in these vessels.

Cited by 23 publications

References 36 publications

Preservation of Endothelium-Dependent Relaxation in Atherosclerotic Mice with Endothelium-Restricted Endothelin-1 Overexpression

Preservation of Endothelium-Dependent Relaxation in Atherosclerotic Mice with Endothelium-Restricted Endothelin-1 Overexpression

Crossroads between peripheral atherosclerosis, western-type diet and skeletal muscle pathophysiology: emphasis on apolipoprotein E deficiency and peripheral arterial disease

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

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