Effect of estradiol metabolites on prostacyclin synthesis in human endothelial cell cultures

Seeger, Harald; Mueck, Alfred O.; Lippert, T. H.

doi:10.1016/s0024-3205(99)00383-5

Cited by 52 publications

(39 citation statements)

References 10 publications

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“…For example, catechol estradiols stimulate endothelial cell prostacyclin production. 39 In insulin-resistant rats, chronic treatment with 2-hydroxyestradiol enhances endothelium-dependent arterial relaxation to acetylcholine. 40 If one considers that AMPK activation is also thought to attenuate insulin resistance, 22 it is attractive to speculate on the findings reported by Tofovic and colleagues, 40 which resulted from 2-hydroxyestradiolmediated AMPK activation.…”

Section: Discussionmentioning

confidence: 99%

Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase

et al. 2005

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Background-Estradiol activates endothelial nitric oxide synthase (eNOS) by mechanisms that involve estrogen receptor-␣ (ER␣), protein kinase B/Akt, mitogen-activated protein kinases, and heat shock protein 90 (HSP90). Recently, AMP-activated protein kinase (AMPK), an enzyme that plays a crucial role in cellular adaptation to metabolic stress, has been implicated in physiological eNOS activation by the hormones adiponectin and insulin. We therefore investigated whether AMPK is activated by estradiol in endothelial cells and plays a role in estradiol-induced eNOS activation. Methods and Results-Porcine aortic endothelial cells exhibited time-and concentration-dependent AMPK activation as determined by phosphorylation of AMPK and its downstream target acetyl coenzyme A carboxylase in response to estradiol (1 nmol/L to 10 mol/L, 1 to 30 minutes). AMPK activation by estradiol was independent of both AMP levels and ER␣ but required estradiol conversion to its catechol metabolites. Estradiol treatment increased eNOS catalytic activity, an effect that was largely reversed when endothelial cells were infected with an AMPK dominant-negative adenovirus. However, inhibition of AMPK did not alter estradiol-induced eNOS phosphorylation at serine 1177 or threonine 495 but decreased eNOS interaction with HSP90. Consistent with this observation, blood vessels from ␣ 1 -AMPK-null mice exhibited defective eNOS-mediated NO production in response to estradiol. Conclusions-Taken together, these data indicate that AMPK activity is essential for estradiol-induced eNOS activation via the promotion of eNOS interaction with HSP90. These data point to a novel role for AMPK in modulating endothelial cell NO bioactivity and HSP90 function.

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Section: Discussionmentioning

confidence: 99%

Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase

et al. 2005

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“…In fact, it has recently been shown that estrone, 2-methoxyestrone, 2-methoxyestradiol, and 16␣-hydroxyestrone, all metabolites of 17␤-estradiol, are potent promoters of PGI 2 synthesis in cultured human umbilical vein endothelial cells. 27 Therefore, it is conceivable that these and other 17␤-estradiol metabolites may subserve a similar role in the living animal.…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol Increases Rat Cerebrovascular Prostacyclin Synthesis by Elevating Cyclooxygenase-1 and Prostacyclin Synthase

Ospina

Krause

Duckles

2002

Stroke

105

102

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Background and Purpose-It has been reported that estrogens modulate peripheral vascular synthesis of vasodilatory hormones, including prostacyclin. If this occurs in the cerebral circulation, it could have important consequences in the modulation of cerebral hemodynamic function and improvement of stroke outcome. We investigated the hypothesis that in vivo 17␤-estradiol treatment of ovariectomized rats increases cerebrovascular prostacyclin production via elevation of the enzymes responsible for prostacyclin synthesis. Methods-Cerebral blood vessels from 17␤-estradiol-treated and nontreated ovariectomized rats were isolated and examined for prostacyclin synthesis by enzyme-linked immunosorbent assay or for protein levels of cyclooxygenase-1, prostacyclin-synthase, and cytosolic phospholipase A 2 by immunoblot analysis. Results-We report that chronic in vivo 17␤-estradiol treatment significantly enhanced basal prostacyclin synthesis in rat cerebral blood vessels by 2.6-fold over control. 17␤-Estradiol treatment also resulted in a 5.1-fold increase of cyclooxygenase-1 protein and a 6.7-fold increase of prostacyclin-synthase protein in the cerebral vasculature. There was no effect of estrogen on levels of cytosolic phospholipase A 2 . Conclusions-Our findings suggest that estrogen influences the biosynthesis of prostacyclin, which may be important in the regulation of cerebral blood flow and thrombosis. This finding may shed light on the mechanisms that govern sex-based differences in cerebrovascular disease. (Stroke. 2002;33:600-605.)

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“…Like the body of experimental information regarding NO-related mechanisms, the results of some studies support a role for vasodilator prostanoids in the acute actions of estrogen (29,30), while others do not (25,27,31). Of some additional interest, many of the studies on peripheral vascular tissue, reporting prostanoid-and/ or NO-dependence, also found that the acute E2 response could be blocked by pretreatment with an estrogen receptor blocker (7, 14, 17 -19, 22).…”

Section: Estrogen and Vasodilationmentioning

confidence: 93%

Estrogen and Cerebrovascular Physiology and Pathophysiology

Pelligrino

Galea

2001

Japanese Journal of Pharmacology

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ABSTRACT-Numerous studies have uncovered a wide variety of estrogen effects with apparent cardiovascular benefits, the most recognized ones being vasodilation, anti-atherogenesis, diminished post-ischemic inflammation and anti-oxidant effects. This article provides an overview of the influence of estrogen on the cerebral vasculature, under physiologic and pathophysiologic conditions, and covers both acute and chronic effects. The discussion is primarily focused on the vasodilatory and anti-inflammatory actions of estrogen, since those particular estrogen influences have received the greatest attention in studies published to date. With respect to vasodilation, although some consideration is given to the role of other vasodilating mechanisms and factors, the emphasis is mostly placed on the endothelial isoform of nitric oxide synthase, eNOS, which has emerged as a clear target of estrogen. Some consideration is given to recent findings that suggest that estrogen can stimulate eNOS activity by decreasing the expression of the eNOS inhibitor caveolin-1. With regard to the ability of estrogen to counteract inflammation, potential mechanisms by which estrogen limits the post-ischemic leukocyte adhesion, and the expression of the inducible NOS, are discussed.

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Effect of estradiol metabolites on prostacyclin synthesis in human endothelial cell cultures

Cited by 52 publications

References 10 publications

Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase

Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase

17β-Estradiol Increases Rat Cerebrovascular Prostacyclin Synthesis by Elevating Cyclooxygenase-1 and Prostacyclin Synthase

Estrogen and Cerebrovascular Physiology and Pathophysiology

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