Inhibition of rat aortic smooth muscle contraction by 2-methoxyestradiol

Gui, Yu; Zheng, Xi-Long; Zheng, Jie; Walsh, Michael P.

doi:10.1152/ajpheart.00723.2008

Cited by 26 publications

(21 citation statements)

References 39 publications

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“…COMT is widely distributed in the hippocampus. It was reported recently that at least some biological effects of E2, such as regulation of smooth muscle cells growth, and cardiovascular protection require its metabolism to 2-ME [18,31]. COMT activity is believed to protect against cardiovascular diseases, degenerative neurological conditions, or estrogeninduced cancers [32,33].…”

Section: Discussionmentioning

confidence: 99%

“…COMT activity is believed to protect against cardiovascular diseases, degenerative neurological conditions, or estrogeninduced cancers [32,33]. Furthermore, 2-ME impacts on various physiological and pathological conditions like muscle contraction or pre-eclampsia [18,31,32,34]. Studies in vitro and in vivo revealed that 2-ME at pharmacological concentrations inhibited the growth of various cancer types, including colon [35], breast [36], or lung [37].…”

Section: Discussionmentioning

confidence: 99%

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Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line

et al. 2015

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2-methoxyestradiol, metabolite of 17β-estradiol, is considered a potential anticancer agent, currently investigated in several clinical trials. This natural compound was found to be effective towards great number of cancers, including colon, breast, lung, and osteosarcoma and has been reported to be relatively non-toxic towards non-malignant cells. The aim of the study was to determine the potential neurotoxicity and genotoxicity of 2-methoxyestradiol at physiological and pharmacological relevant concentrations in hippocampal HT22 cell line. Herein, we determined influence of 2-methoxyestradiol on proliferation, inhibition of cell cycle, induction of apoptosis, and DNA damage in the HT22 cells. The study was performed using imaging cytometry and comet assay techniques. Herein, we demonstrated that 2-methoxyestradiol, at pharmacologically and also physiologically relevant concentrations, increases nuclear localization of neuronal nitric oxide synthase. It potentially results in DNA strand breaks and increases in genomic instability in hippocampal HT22 cell line. Thus, we are postulating that naturally occurring 2-methoxyestradiol may be considered a physiological modulator of neuron survival.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line

et al. 2015

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“…Indeed, endothelial ER stimulation induces vascular wall dilation 16,18 mainly through an increased nitric oxide production 45 due to rapid eNOS activation 18,46,47 or induction of eNOS expression. 17 E2 has also been shown to stimulate endothelial cell survival and formation of primary capillary tube. 48 At the media level, E2 regulates smooth muscle cell proliferation, 12 differentiation, apoptosis, 49 and even contraction.…”

Section: Discussionmentioning

confidence: 99%

“…48 At the media level, E2 regulates smooth muscle cell proliferation, 12 differentiation, apoptosis, 49 and even contraction. 17 The mechanisms underlying these effects are poorly described, implicating ERK/MAPKs and p38/SAPKs2 balance or PI3K-Akt and Src signaling, and cannot explain all the E2 effects. 47,49,50 Recently, although the mechanism involved has not been identified, it has been suggested that inhibition of Rho-Rock pathway in the central nervous system or in the vasculature might participate to the limitation of arterial contraction induced by E2.…”

Section: Discussionmentioning

confidence: 99%

AMPK Alpha 1-Induced RhoA Phosphorylation Mediates Vasoprotective Effect of Estradiol

Gayard

Guilluy

Rousselle

et al. 2011

ATVB

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Objective-Estradiol (E2) mediates numerous beneficial effects assigned to estrogens, but whereas mechanisms have been described at the endothelial level, direct effects on vascular smooth muscle cells (VSMC) are poorly documented. As evidence accumulates regarding the role of RhoA in vascular pathophysiology and the benefit of RhoA-Rho associated protein kinase (Rock) pathway inhibition, we analyzed if E2 could inhibit it in VSMC. Methods and Results-We show that in VSMC, E2 inhibits the RhoA-Rock pathway in a time-and concentrationdependent manner. The inhibition of RhoA-Rock pathway results from E2-induced phosphorylation of the Ser188 of RhoA. Using pharmacological, transfection, and in vitro phosphorylation experiments, we demonstrate that AMP-activated protein kinase subunit alpha 1 (AMPK␣1) is activated by estrogen receptor stimulation and catalyzes RhoA phosphorylation induced by E2. Ex vivo, ovariectomy leads to an increase in the amplitude of phenylephrine-or serotonine-induced contractions of aortic rings in wild-type mice but not in AMPK␣1-knock-out mice or E2-supplemented animals. These functional effects were correlated with a reduced level of RhoA phosphorylation in the aorta of ovariectomized female, male, and AMPK␣1 knock-out mice. Conclusion-Our work thus defines AMPK␣1 as (1) a new kinase for RhoA and (2) Key Words: cell physiology Ⅲ g proteins Ⅲ signal transduction Ⅲ vasoconstriction Ⅲ estrogen I n the vasculature, RhoA and its downstream effector Rho associated protein kinase (Rock) have been shown to regulate processes such as vascular smooth muscle cell (VSMC) contraction, proliferation and differentiations, endothelial permeability, platelet activation, and leukocyte migration. 1 Accordingly, basal RhoA activity is required for homeostatic functions in physiological conditions, but its sustained overactivation has pathological consequences in the vascular system, particularly in VSMC. Activation of RhoAdependent pathways is involved in excessive contraction, and thereby increases blood pressure, but also in excessive cell growth and migration that participate in pathological cardiovascular remodeling. 2 Several regulatory proteins thus cooperate to provide a tight control of RhoA activity including RhoA exchange factors and RhoA GTPase activating proteins that control the GDP/GTP cycle, and Rho guanine dissociation inhibitor (RhoGDI) that sequesters RhoA in the cytosol. 3 In addition to this regulation and independently of GDP-GTP cycling, recent reports have proposed that phosphorylation/ dephosphorylation cycle also controls Rho protein activity. cAMP-and cyclic GMP-dependent protein kinases (PKA and PKG) phosphorylate RhoA on Ser188. 4,5 Both in vitro and in vivo experiments indicated that Ser188 phosphorylation of RhoA induces increased association to GDI leading to cytosolic accumulation of RhoA, 6 inhibition of RhoA-mediated target activation and functions 7 and vasodilation. 5 Recently, we showed that stimulation of angiotensin II type 2 receptor (AT 2 R) in VSMC induces RhoA ph...

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“…2ME inhibits proliferation and induces apoptosis in vascular smooth muscle cells (SMCs) in vivo and in vitro, most likely via affecting centrosome and mitotic spindles (Barchiesi et al, 2006;Gui and Zheng, 2006). 2ME also inhibits smooth muscle contraction through endothelial nitric oxide release (Gui et al, 2008). Animal studies demonstrate that 2ME attenuates the development of hypertension and its complications, involving suppression of superoxide production, inflammatory responses and arterial remodeling (Bonacasa et al, 2008).…”

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confidence: 99%

2‐methoxyestradiol inhibits atorvastatin‐induced rounding of human vascular smooth muscle cells

Yin

Gui

Zheng

2009

Journal Cellular Physiology

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The cardiovascular benefits of statins, including atorvastatin (ATV), have been reported to be gender-dependent, but the underlying mechanism is unclear. In this study we examine whether estrogen and its metabolite, 2-methoxyestradiol (2ME), affect the rounding response of human vascular smooth muscle cells (SMCs) induced by ATV. Twenty-four hour treatment with ATV (10-100 microM) induced rounding of cultured human SMCs. Addition of 2ME (1-20 microM), but not 17beta-estradiol, for 2 h induced re-spreading of rounded cells. Our further studies showed that the effects of 2ME were mimicked by microtubule-disrupting drugs and inhibited by taxol. Inhibition of RhoA and ROCK (Rho-kinase) by C3-toxin and H-1152, respectively, blocked 2ME effects. 2ME effects were also blocked by treatment with either actin-interfering drugs, such as cytochalasin D and jasplakinolide, or myosin inhibitor blebbistatin. ML-7 and -9, the inhibitors for myosin light chain kinase, inhibited 2ME effect as well. ATV treatment induced a decrease of F-actin content and Thr18/Ser19 dual phosphorylation of myosin regulatory light chain (MRLC), which was rescued by 2ME or mevalonate. The rescue effects of 2ME on F-actin content and MRLC dual phosphorylation were abolished by taxol or H-1152. In addition, kinesin Eg5 inhibitor monastrol and dynein inhibitor erythro-9-3-(2-hydroxynonyl) adenine (EHNA) significantly blocked 2ME effects. Finally, our results revealed that 2ME inhibited the migration of SMCs induced by ATV (0.1 microM) in wound healing assay and Boyden chamber assay. In summary, our data show that 2ME, but not estrogen, inhibits ATV-induced rounding of human SMCs through induction of microtubule disassembly and activation of the Rho-ROCK-actinomyosin pathway.

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Inhibition of rat aortic smooth muscle contraction by 2-methoxyestradiol

Cited by 26 publications

References 39 publications

Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line

Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line

AMPK Alpha 1-Induced RhoA Phosphorylation Mediates Vasoprotective Effect of Estradiol

2‐methoxyestradiol inhibits atorvastatin‐induced rounding of human vascular smooth muscle cells

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