Endothelial Estrogen Receptor-α Plays a Crucial Role in the Atheroprotective Action of 17β-Estradiol in Low-Density Lipoprotein Receptor-Deficient Mice
Endothelial Estrogen Receptor-α Plays a Crucial Role in the Atheroprotective Action of 17β-Estradiol in Low-Density Lipoprotein Receptor-Deficient Mice
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DOI：
10.1161/circulationaha.109.898445
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发表时间：
2009-12-22
期刊：
影响因子：
37.8
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
背景-雌激素对早期动脉粥样硬化的预防在所有动物模型中都得到了明确的证明，并且似乎是通过对动脉壁的直接作用而不是通过对脂蛋白谱的影响来调节的。本研究的目的是评估哪个细胞靶点在雌激素的这一有益作用中起关键作用。方法和结果-我们首先证实了雌激素受体-α(ERα)在雌激素的动脉粥样硬化保护作用中的关键作用，因为这一作用在低密度脂蛋白受体(LDLR)和ERα缺乏的小鼠中完全取消。其次，使用在造血系中存在ERα缺陷的嵌合小鼠，我们发现雌二醇的保护作用持续存在，这表明造血外ERα参与了这一过程。第三，我们发现，在LDLR-/-背景下与Tie2-Cre(+)小鼠培育的loxP侧翼ERα小鼠(ERα(FLOX/FLOX))在大多数造血细胞和所有内皮细胞中完全失活ERα。值得注意的是，在这个小鼠模型中，雌二醇的动脉粥样硬化保护作用被完全消除。第四，在植入Tie2-Cre(+)ERα(Flox/Flox)或ERα(-/-)骨髓的LDLR-/-小鼠中，雌二醇的动脉粥样硬化保护作用仍然消失，而在表达内皮ERα的类似嵌合体Tie2-Cre(-)ERα(Flox/Flox)LDLR-/-受体中，雌激素的保护作用仍然存在。结论：我们首次直接地证明了内皮ERα是雌激素动脉粥样硬化保护作用的关键靶点，而造血ERα是必不可少的。现在应该考虑选择性雌激素受体调节剂来模拟雌激素的内皮作用，以保护动脉粥样硬化。(发行量。2009；120：2567-2576。)
Background-The prevention of early atheroma by estrogens has been clearly demonstrated in all animal models and appears to be mediated through a direct action on the arterial wall rather than through an effect on the lipoprotein profile. The goal of the present study was to evaluate which cellular target is crucial in this beneficial action of estradiol.Methods and Results-We first confirmed the key role of estrogen receptor-alpha (ER alpha) in the atheroprotective effect of estradiol, because this action was completely abolished in mice deficient in both the low-density lipoprotein receptor (LDLr) and ER alpha. Second, using chimeric mice with an ER alpha deficiency in the hematopoietic lineage, we showed the persistence of the protective action of estradiol, which suggests the involvement of extrahematopoietic ER alpha. Third, we showed that loxP-flanked ER alpha mice (ER alpha(flox/flox)) bred with Tie2-Cre(+) mice on an LDLr-/- background had complete inactivation of ER alpha in most hematopoietic and all endothelial cells. Remarkably, in this mouse model, the atheroprotective effect of estradiol was completely abolished. Fourth, the atheroprotective effect of estradiol remained abolished in Tie2-Cre(+) ER alpha(flox/flox) LDLr-/- mice transplanted with either Tie2-Cre(+) ER alpha(flox/flox) or ER alpha(-/-) bone marrow, whereas it was present in analogous chimeric Tie2-Cre(-) ER alpha(flox/flox) LDLr-/- receivers expressing endothelial ER alpha.Conclusions-We demonstrate directly and for the first time that endothelial ER alpha represents a key target of the atheroprotective effect of estradiol, whereas hematopoietic ER alpha is dispensable. Selective estrogen receptor modulators that mimic the endothelial action of estradiol should now be considered in atheroprotection. (Circulation. 2009;120:2567-2576.)