The transactivating function 1 of estrogen receptor α is dispensable for the vasculoprotective actions of 17β-estradiol
The transactivating function 1 of estrogen receptor α is dispensable for the vasculoprotective actions of 17β-estradiol
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DOI：
10.1073/pnas.0808742106
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发表时间：
2009-02-10
影响因子：
11.1
通讯作者：
Arnal, Jean-Francois
中科院分区：
文献类型：
--
作者：
Billon-Gales, Audrey;Fontaine, Coralie;Arnal, Jean-Francois
全长66 kDa雌激素受体α（ER α）通过两个激活功能（AF）刺激靶基因转录，即N-末端结构域中的AF-1和配体结合结构域中的AF-2。另一种生理表达的46-kDa ER α同种型缺乏N-末端A/B结构域，因此缺乏AF-1。以前的研究表明，在培养的内皮细胞的N-末端A/B结构域可能不需要雌二醇（E2）引起的NO的生产。为了评估ER α AF-1参与E2的血管保护作用，我们在小鼠中产生了ER α A/B结构域的靶向缺失。在这些ER α AF-1（0）小鼠中，基础内皮NO产生和再内皮化过程均被E2给药增加，其程度与对照小鼠相似。此外，外源性E2同样减少了卵巢切除18周龄ER α AF-1（+/+）LDLr-/-（低密度脂蛋白受体）和ER α AF-1（0）LDLr-/-小鼠主动脉根部的脂肪条纹沉积，这些小鼠喂食高胆固醇血症饮食。此外，对8月龄卵巢切除或完整雌性小鼠主动脉树的正面制备物上的病变大小进行定量，揭示ER α AF-1与内源性雌激素的动脉粥样硬化保护作用有关。我们的结论是，ER α AF-1是不需要E2的三个主要的血管保护作用，而它是必要的E2对生殖目标的影响。因此，选择性ER调节剂刺激ER α，使ER α AF-1的活化最小化，可以保留有益的血管作用，同时使性效应最小化。生理学
Full-length 66-kDa estrogen receptor alpha(ER alpha) stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal domain and AF-2 in the ligand binding domain. Another physiologically expressed 46-kDa ER alpha isoform lacks the N-terminal A/B domains and is consequently devoid of AF-1. Previous studies in cultured endothelial cells showed that the N-terminal A/B domain might not be required for estradiol (E2)-elicited NO production. To evaluate the involvement of ER alpha AF-1 in the vasculoprotective actions of E2, we generated a targeted deletion of the ER alpha A/B domain in the mouse. In these ER alpha AF-1(0) mice, both basal endothelial NO production and reendothelialization process were increased by E2 administration to a similar extent than in control mice. Furthermore, exogenous E2 similarly decreased fatty streak deposits at the aortic root from both ovariectomized 18-week-old ER alpha AF-1(+/+) LDLr-/- (low-density lipoprotein receptor) and ER alpha AF-1(0) LDLr-/- mice fed with a hyper-cholesterolemic diet. In addition, quantification of lesion size on en face preparations of the aortic tree of 8-month-old ovariectomized or intact female mice revealed that ER alpha AF-1 is dispensable for the atheroprotective action of endogenous estrogens. We conclude that ER alpha AF-1 is not required for three major vasculoprotective actions of E2, whereas it is necessary for the effects of E2 on its reproductive targets. Thus, selective ER modulators stimulating ER alpha with minimal activation of ER alpha AF-1 could retain beneficial vascular actions, while minimizing the sexual effects. PHYSIOLOGY