Estradiol Relaxes Rat Aorta via Endothelium-Dependent and -Independent Mechanisms

Abou-Mohamed, Gamal; Elmarakby, Ahmed A.; Carrier, Gerald O.; Catravas, John D.; Caldwell, Robert W.; White, Richard E.

doi:10.1159/000071268

Cited by 13 publications

(6 citation statements)

References 26 publications

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“…It is important to note, however, that the effective concentrations of 2-ME in our in vitro experiments are considerably higher than the picomolar to tens of nanomolar concentrations found in normal human plasma (6). The effective concentrations of 2-ME for the inhibition of PE-induced contraction observed in the present in vitro study lie in the micromolar range, i.e., similar to the effective concentrations of estrogen for the inhibition of contraction reported by others (1,4,16,24,32). These concentrations are also consistent with those required for the 2-ME induction of antiproliferative activity in cultured cells (5,12,22,38).…”

Section: Discussionsupporting

confidence: 84%

“…On the other hand, if the endothelium is absent, E 2 can directly inhibit smooth muscle contraction independent of NO production. Endothelium-dependent and -independent mechanisms have been previously found in E 2 -induced relaxation of aortic rings (1,21). Importantly, the present study demonstrated that 2-ME inhibited smooth muscle contraction at concentrations similar to the effective concentrations of E 2 on inhibition of contraction as reported by others (10, 16, 21, 32).…”

Section: Discussionmentioning

confidence: 86%

“…-nitro-L-arginine methyl ester hydrochloride (L-NAME), Taxol, nocodazole, 1-{4-(6-bromobenzo [1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl}-ethanone (G-1), 1-aminobenzotriazole (ABT), 2Ј-fluoro-3,4-dihydroxy-5-nitrobenzophenone (Ro 41-0960), and ACh chloride were purchased from Sigma-Aldrich Canada (Oakville, ON, Canada).…”

Section: Materials 2-me E2 Fulvestrant (Ici-182780) Actinomycin Dmentioning

confidence: 99%

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Inhibition of rat aortic smooth muscle contraction by 2-methoxyestradiol

Gui

Zheng²,

Zheng³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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studies suggest that 2-methoxyestradiol (2-ME), an estrogen metabolite, has a similar inhibitory effect as 17␤-estradiol (E 2) on vascular tone. However, it is not known whether 2-ME mediates the effects of E 2 or by what mechanism 2-ME regulates smooth muscle contraction. Therefore, we compared the effects of 2-ME and E 2 on rat aortic smooth muscle contraction. A preincubation with 2-ME (10 M) for 1 h inhibited phenylephrine (PE)-induced tension in endothelium-intact, but not -denuded, tissues, whereas E 2 inhibited PE-induced contraction in both preparations. The effects of 2-ME and E 2 on endothelium-intact preparations were prevented by L-NAME hydrochloride (a nitric oxide synthase inhibitor). The 2-ME treatment reduced PE-induced phosphorylation of the 20-kDa myosin regulatory light chain. The inhibitory effects of 2-ME and E 2 were not affected by ICI-182780 (an estrogen receptor antagonist) or actinomycin D (a gene transcription inhibitor); however, the effect of 2-ME, but not E 2, was prevented by cycloheximide (a protein synthesis inhibitor). Furthermore, the effect of E 2 was not blocked by 1-aminobenzotriazole (a cytochrome P-450 inhibitor) or Ro 41-0960 (a catechol-O-methyltransferase inhibitor). The effect of 2-ME was not mimicked by microtubuleinterfering agents (nocodazole or Taxol). We conclude that 2-ME inhibits smooth muscle contractility through an endothelium-and nitric oxide-dependent mechanism, which does not involve estrogen receptors or microtubule disruption. The effect of 2-ME, but not E 2, involves de novo protein synthesis. 2-ME does not mediate the inhibitory effect of E2 on smooth muscle contraction. These results support a potentially important role of 2-ME in the regulation of smooth muscle tone in the vasculature.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 86%

Section: Materials 2-me E2 Fulvestrant (Ici-182780) Actinomycin Dmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of rat aortic smooth muscle contraction by 2-methoxyestradiol

Gui

Zheng²,

Zheng³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…These include studies on isolated arteries from rats (aorta, coronary, and mesenteric arteries; see Refs. 1,36,39,48), rabbit carotid artery (46), mouse aorta (13), coronary microvessels from female or male dogs (24), and human vessels, including coronary arteries (11) and from our laboratory small subcutaneous arteries from men (unpublished data). In contrast, others have implied that NO plays a role in the acute dilation to 17␤-E 2 in, for example, isolated female coronary arteries (4,11), aorta and femoral arteries from rat (5, 51), human mammary artery (38), rabbit coronary artery, and uterine arteries from sheep (44,55).…”

Section: Discussionmentioning

confidence: 99%

Dilatory responses to estrogenic compounds in small femoral arteries of male and female estrogen receptor-β knockout mice

Cruz¹,

Douglas

Gustafsson

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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The objectives of this study were to determine whether acute dilatory responses to estrogen receptor agonists are altered in isolated arteries from estrogen receptor beta-deficient mice (beta-ERKO) and to gain insight into the role of nitric oxide (NO) in these responses. Femoral arteries (approximately 250 microm) from male and female beta-ERKO mice and wild-type (WT) littermates (26 female, 13 in each group; and 24 male, 12 in each group) were mounted on a Multi-Myograph. Concentration-response curves to 17beta-estradiol (17beta-E2) and the selective estrogen receptor-alpha (ER-alpha) agonist propyl-[1H]-pyrazole-1,3,5-triy-trisphenol (PPT) were obtained before and after NO synthase (NOS) inhibition [Nomega-nitro-L-arginine methyl ester (L-NAME), 0.1 mM] in arteries preconstricted with U-46619 (a thromboxane analog). In WT mice, responses to the potent estrogen receptor-beta (ER-beta) agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) and the contribution of NO were also assessed. Concentration-response curves to 17beta-E2 and PPT were similar in arteries from WT and -ERKO mice of both genders, but NO-mediated relaxation was different, since L-NAME reduced 17-E2 mediated relaxation in arteries from male and female beta-ERKO but not WT mice (P < 0.05). NOS inhibition reduced dilation to PPT in arteries from male and female WT mice, as well as arteries from female beta-ERKO mice (P < 0.05). Responses to DPN in arteries from WT female and male mice did not differ after NOS inhibition. The acute dilatory responses to estrogenic compounds are similar in WT and beta-ERKO mice but differ mechanistically. Because NO appeared to contribute to responses to 17beta-E2 in arteries from beta-ERKO but not WT mice, the presence of ER- apparently inhibits ER--mediated NO relaxation.

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“…The presence of these consensus sites is consistent with evidence showing that levels of eNOS transcripts are elevated by sheer stress (Davis et al, 2001; Woodman et al, 2005), exercise (Sessa et al, 1994; Yang et al, 2002) and hypoxia (Le Cras et al, 1996). Regulation of eNOS transcription by estrogens is still a matter of debate (Arnal et al, 1996; Kleinert et al, 1998), however, estradiol relaxes rat aortic segments via endothelium-dependent and -independent mechanisms involving the NO-cGMP signaling system (Abou-Mohamed et al, 2003). Both lipopolysaccharide (Arriero et al, 2000) and tumor necrosis factor-α (Yoshizumi et al, 1993) decrease eNOS gene expression by reducing the stability of eNOS mRNAs.…”

Section: Transcriptional and Post-transcriptional Regulation Of Enos mentioning

confidence: 99%

Endothelial nitric oxide (NO) and its pathophysiologic regulation

Chatterjee¹,

Catravas²

2008

Vascular Pharmacology

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211

163

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Nitric oxide (NO) is a gaseous lipophilic free radical generated by three distinct isoforms of nitric oxide synthases (NOS), type 1 or neuronal (nNOS), type 2 or inducible (iNOS) and type 3 or endothelial NOS (eNOS). Expression of eNOS is altered in many types of cardiovascular disease, such as atherosclerosis, diabetes and hypertension. The ubiquitous chaperone heat shock protein 90 (hsp90) associates with NOS and is important for its proper folding and function. Current studies point toward a therapeutic potential by modulating hsp90-NOS association in various vascular diseases. Here we review the transcriptional regulation of endothelial NOS and factors affecting eNOS activity and function, as well as the important vascular pathologies associated with altered NOS function, focusing on the regulatory role of hsp90 and other factors in NO-associated pathogenesis of these diseases. Keywords nitric oxide; hsp90; cardiovascular disease Transcriptional and post-transcriptional regulation of eNOS in endothelial cellsEndothelial cells have a constitutive expression of eNOS and like other constitutively expressed proteins, the eNOS promoter lacks the typical TATA box. Instead, it has other multiple cisregulatory DNA sequences like SP-1, GATA, activator protein-1, activator protein-2, nuclear factor-1, sheer stress response elements and sterol-regulatory elements (Marsden et al., 1993). The presence of these consensus sites is consistent with evidence showing that levels of eNOS transcripts are elevated by sheer stress (Davis et al., 2001;Woodman et al., 2005), exercise (Sessa et al., 1994;Yang et al., 2002) and hypoxia (Le Cras et al., 1996). Regulation of eNOS transcription by estrogens is still a matter of debate (Arnal et al., 1996;Kleinert et al., 1998), however, estradiol relaxes rat aortic segments via endothelium-dependent andindependent mechanisms involving the NO-cGMP signaling system (Abou-Mohamed et al., 2003). Both lipopolysaccharide (Arriero et al., 2000) and tumor necrosis factor-α (Yoshizumi et al., 1993) decrease eNOS gene expression by reducing the stability of eNOS mRNAs. Basal human eNOS transcription is controlled by two regulatory regions, the positive regulatory Address correspondence to: Dr. John D. Catravas Vascular Biology Center Medical College of Georgia Augusta, GA 30912-2500 USA e-mail: jcatrava@mcg.edu tel: +1-706-721-6338 fax: +1-706-721-9799. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Searles, 2006). Moreover, these regions also contain differentially methylated nucleotides that restrict eNOS transcription largely in vascular endothel...

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Estradiol Relaxes Rat Aorta via Endothelium-Dependent and -Independent Mechanisms

Cited by 13 publications

References 26 publications

Inhibition of rat aortic smooth muscle contraction by 2-methoxyestradiol

Inhibition of rat aortic smooth muscle contraction by 2-methoxyestradiol

Dilatory responses to estrogenic compounds in small femoral arteries of male and female estrogen receptor-β knockout mice

Endothelial nitric oxide (NO) and its pathophysiologic regulation

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