0333 : Tissue specificity of the membrane vs nuclear actions of estrogen receptor alpha: insights from targeted mutations in mouse models

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• 作者：Jean-Franç ; ois Arnal ; ^{jean-francois.arnal@inserm.fr" class="auth_mail" title="E-mail the corresponding author} ; Coralie Fontaine ; Marie-Cecile Valera ; Marine Adlanmerini ; Pierre Gourdy ; Franç ; oise Lenfant
• 刊名：Archives of Cardiovascular Diseases Supplements
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：8
• 期：3
• 页码：217
• 全文大小：51 K

文摘

Thanks to unique mouse models, we demonstrated that the estrogen receptor alpha (ERa), but not ERb, is absolutely necessary for most of the arterial and metabolic actions of 17b-estradiol (E2). Estrogens also elicit deleterious effects on the uterus and breast (partly via their proliferative effect which increases the risk of cancer) as well as increased risk of venous thromboembolism, which are the two main limitations of classic estrogen therapies. ER contains two independent transactivation functions AF-1 and AF-2, and our team dissected for the first time in vivo the roles of functions ERaAF-1 and AF-2, allowing to define the key role of these nuclear actions in several tissues. More recently, we reported the key role of the ERa fraction localized to the plasma membrane which is absolutely necessary for the protective endothelial actions of E2 as well as, more unexpectedly, for female fertility. One mystery of estrogens biology is that selective ER modulators (SERMs, such as tamoxifen, raloxifen) have a highly tissue-specific action, behaving as agonists in some tissues (such as bone) and as antagonist in others (breast). We will report how these mouse models allowed us to characterize:

1)

the tissue-specific roles of ERa : membrane ERa mediates the effect of E2 in the endothelium (acceleration of reendothelialization, activation of endothelial NO synthase), whereas nuclear ERa mediates the effect of E2 in the uterus.

2)

a new natural SERM (Estetrol) currently tested in a phase III clinical trial as a safer oral contraception or hormonal treatment of menopause, as this molecule does not alter the hepatic-derived coagulation factors, and thereby could not increase the venous thrombosis risk.

3)

an Estrogen Dendrimer Conjugate, a selective activator of membrane ERa, which could be a new endothelial protective SERM.

The author declares a conflict of interest: JF Arnal’team received a financial support from Uteron/Mithra to study the mechanisms of action of Estetrol.