Gender Differences in Coronary Artery Diameter Involve Estrogen, Nitric Oxide, and Ca
            <sup>2+</sup>
            -Dependent K
            <sup>+</sup>
            Channels

Wellman, George C.; Bonev, Adrian D.; Nelson, Mark T.; Brayden, Joseph E.

doi:10.1161/01.res.79.5.1024

Cited by 229 publications

(207 citation statements)

References 39 publications

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“…111 Furthermore, increases in intravascular pressure elicited smaller myogenic constrictions in isolated rat coronary arteries from females compared to males, and the larger diameters of the female coronary arteries were associated with higher endothelial Ca 2+ concentrations and eNOS activity. 112 Elevated NO release from female compared to male coronary arteries has been observed in a number of studies, [113][114][115] and is consistent with findings in a variety of other artery types.…”

Section: Dovepresssupporting

confidence: 77%

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Levy

Chung²,

Kroetsch

et al. 2009

VHRM

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This review highlights a number of nitric oxide (NO)-related mechanisms that contribute to coronary vascular function and that are likely affected by hypertension and thus become important clinically as potential considerations in prevention, diagnosis, and treatment of coronary complications of hypertension. Coronary vascular resistance is elevated in hypertension in part due to impaired endothelium-dependent function of coronary arteries. Several lines of evidence suggest that other NO synthase isoforms and dilators other than NO may compensate for impairments in endothelial NO synthase (eNOS) to protect coronary artery function, and that NO-dependent function of coronary blood vessels depends on the position of the vessel in the vascular tree. Adaptations in NOS isoforms in the coronary circulation to hypertension are not well described so the compensatory relationship between these and eNOS in hypertensive vessels is not clear. It is important to understand potential functional consequences of these adaptations as they will impact the efficacy of treatments designed to control hypertension and coronary vascular disease. Polymorphisms of the eNOS gene result in significant associations with incidence of hypertension, although mechanistic details linking the polymorphisms with alterations in coronary vasomotor responses and adaptations to hypertension are not established. This understanding should be developed in order to better predict those individuals at the highest risk for coronary vascular complications of hypertension. Greater endothelium-dependent dilation observed in female coronary arteries is likely related to endothelial Ca 2+ control and eNOS expression and activity. In hypertension models, the coronary vasculature has not been studied extensively to establish mechanisms for sex differences in NO-dependent function. Genomic and nongenomic effects of estrogen on eNOS and direct and indirect antioxidant activities of estrogen are discussed as potential mechanisms of interest in coronary circulation that could have implications for sex-and estrogen status-dependent therapy for hypertension and coronary dysfunction. The current review identifies some important basic knowledge gaps and speculates on the potential clinical relevance of hypertension adaptations in factors regulating coronary NO function.

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Section: Dovepresssupporting

confidence: 77%

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Levy

Chung²,

Kroetsch

et al. 2009

VHRM

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“…Increases in repolarizing current and open-state probability, as well as decreases in unitary conductance, have been demonstrated (12,15,29). In our experiments the effects of 17␤-estradiol on maxi-K channel expression were consistently inhibitory over a wide range of concentrations, whereas 17␣-estradiol inhibited expression only at a high concentration.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism by which estrogen interacts with this channel is unknown. However, both 17␤-estradiol and tamoxifen, a partial agonist of nuclear estradiol receptors, have been shown to activate maxi-K channels in both heterologous expression systems and smooth muscle cells, resulting in greater repolarizing currents (12,13). Because acute incubation with either 17␤-estradiol or membrane-impermeable estrogen derivatives activate maxi-K channels, signal transduction pathways other than those mediated by classical nuclear estradiol receptors ␣ (ER␣) 1 or ␤ (ER␤) are likely to be involved.…”

mentioning

confidence: 99%

Estradiol Binding to Maxi-K Channels Induces Their Down-regulation via Proteasomal Degradation

Korovkina

Brainard

Ismail

et al. 2004

Journal of Biological Chemistry

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Estrogens exert their biological action via both genomic and non-genomic mechanisms. Proteins different from classical estradiol receptors are believed to mediate the latter effects. Here we demonstrate that the maxi-K channel functions as an estrogen-binding protein in transfected HEK293 cells. Whole-cell maxi-K channel currents and protein expression were attenuated by exposure to either 17␣-or 17␤-estradiol. This effect was dose-dependent for 17␤-estradiol at concentrations ranging from 10 nM to 1 M, while 17␣-estradiol inhibited channel expression only at 1 M. These effects were mediated by direct low affinity binding of estradiol to the maxi-K channel but not to its accessory ␤1-subunit, as revealed by cell membrane estradiol binding assays. However, specific binding of estradiol to the channel was facilitated by the presence of the ␤1 subunit. Addition of MG-132, a blocker of proteasomal degradation, stabilized channel expression. These data suggest that channel down-regulation is mediated by estrogen-induced proteasomal degradation, similar to the pathway used for estrogen receptor degradation. Membrane expression of endogenous maxi-K channels in cultured vascular smooth muscle cells was also attenuated by prolonged exposure to 17␣-and 17␤-estradiol. Thus our studies demonstrate that estrogen binds to maxi-K channels and may directly regulate channel expression and function. These results will have important implications in understanding estradiol-induced effects in multiple tissues including vascular smooth muscle.Existing epidemiological data suggest a beneficial role for estrogens in maintaining cardiovascular protection in pre-menopausal women. However, other data show that estrogen-containing preparations can negatively affect the health of premenopausal as well as post-menopausal women (1-6). These results indicate the existence of complex estradiol-signaling mechanisms, possibly mediated by proteins other than classical intracellular estradiol receptors (7).One protein that has been hypothesized to be a potential effector of the action of estrogen is the large conductance Ca 2ϩ -and voltage-activated K ϩ channel (maxi-K channel). This channel provides a buffering repolarizing current in response to various physiological stimuli (8 -11). The mechanism by which estrogen interacts with this channel is unknown. However, both 17␤-estradiol and tamoxifen, a partial agonist of nuclear estradiol receptors, have been shown to activate maxi-K channels in both heterologous expression systems and smooth muscle cells, resulting in greater repolarizing currents (12, 13). Because acute incubation with either 17␤-estradiol or membrane-impermeable estrogen derivatives activate maxi-K channels, signal transduction pathways other than those mediated by classical nuclear estradiol receptors ␣ (ER␣) 1 or ␤ (ER␤) are likely to be involved. Valverde et al. (14) showed that activation of maxi-K channels by 17␤-estradiol occurs when the channel is associated with its accessory ␤1-subunit. This effect was not observed in t...

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“…Such activation occurs through a pathway dependent on nitric oxide (NO) and cGMP. 27 Furthermore, most of the actions of ANF are mediated through activation of its transmembrane GC-A receptor. 28 Receptorgenerated cGMP binds to cGK, which is thought to mediate the principal biological functions of cGMP.…”

Section: Cgmp-dependent Protein Kinase and Cardiomyocyte Hypertrophymentioning

confidence: 99%

17β-Estradiol Antagonizes Cardiomyocyte Hypertrophy by Autocrine/Paracrine Stimulation of a Guanylyl Cyclase A Receptor-Cyclic Guanosine Monophosphate-Dependent Protein Kinase Pathway

et al. 2004

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Background-Significant gender-related differences exist in the development of left ventricular hypertrophy (LVH). In addition, administration of 17␤-estradiol (E 2 ) to ovariectomized female mice attenuates the development of LVH, demonstrating an antagonistic role for E 2 in this process, although no molecular mechanism has been proposed for this phenomenon. Methods and Results-E 2 attenuated phenylephrine and endothelin-1 induced hypertrophy in neonatal cardiomyocytes, and E 2 directly induced atrial natriuretic factor (ANF) expression as assessed by Northern blot, immunocytochemical analyses, and transient transfection assays using ANF promoter deletion fragments. Both the antihypertrophic effects and ANF induction could be blocked by the estrogen receptor antagonist ICI 182,780, which demonstrates a genomic, estrogen receptor-dependent pathway. To mimic E 2 -induced autocrine/paracrine effects through stimulation of the guanylyl cyclase A receptor (ANF receptor), cardiomyocytes were stimulated with phenylephrine or endothelin-1 in the presence of exogenous ANF or 8-bromo-cyclic guanosine monophosphate (cGMP), both of which attenuated agonist-induced hypertrophy. Both estrogen and ANF increased cGMP activity. The antihypertrophic effect of ANF could be reduced with extracellular ANF antibodies in a dose-dependent manner. cGMP-dependent protein kinase mediates the antihypertrophic effects of E 2 , so cardiomyocytes were agonist stimulated in the presence of the cGMP-dependent protein kinase blocker KT-5823. KT-5823 not only reversed the antihypertrophic properties of E 2 , ANF, or 8-bromo-cGMP, but also evoked potentiation of hypertrophy. Conclusions-E 2 -mediated induction of ANF in cardiac hypertrophy contributes to its antagonistic effects in LVH.

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Gender Differences in Coronary Artery Diameter Involve Estrogen, Nitric Oxide, and Ca ²⁺ -Dependent K ⁺ Channels

Cited by 229 publications

References 39 publications

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Estradiol Binding to Maxi-K Channels Induces Their Down-regulation via Proteasomal Degradation

17β-Estradiol Antagonizes Cardiomyocyte Hypertrophy by Autocrine/Paracrine Stimulation of a Guanylyl Cyclase A Receptor-Cyclic Guanosine Monophosphate-Dependent Protein Kinase Pathway

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Gender Differences in Coronary Artery Diameter Involve Estrogen, Nitric Oxide, and Ca 2+ -Dependent K + Channels

Cited by 229 publications

References 39 publications

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Estradiol Binding to Maxi-K Channels Induces Their Down-regulation via Proteasomal Degradation

17β-Estradiol Antagonizes Cardiomyocyte Hypertrophy by Autocrine/Paracrine Stimulation of a Guanylyl Cyclase A Receptor-Cyclic Guanosine Monophosphate-Dependent Protein Kinase Pathway

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Gender Differences in Coronary Artery Diameter Involve Estrogen, Nitric Oxide, and Ca ²⁺ -Dependent K ⁺ Channels