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- Vinel, A., et al.
(författare)
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Role of ERalpha in the Effect of Estradiol on Cancellous and Cortical Femoral Bone in Growing Female Mice
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 157:6, s. 2533-2544
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor-alpha (ER alpha) acts primarily in the nucleus as a transcription factor involving two activation functions, AF1 and AF2, but it can also induce membrane-initiated steroid signaling (MISS) through the modulation of various kinase activities and/or secondary messenger levels. Previous work has demonstrated that nuclear ER alpha is required for the protective effect of the estrogen 17 beta-estradiol (E2), whereas the selective activation of ER alpha MISS is sufficient to confer protection in cortical but not cancellous bone. The aim of this study was to define whether ER alpha MISS is necessary for the beneficial actions of chronic E2 exposure on bone. We used a mouse model in which ER alpha membrane localization had been abrogated due to a point mutation of the palmitoylation site of ER alpha (ER alpha-C451A). Alterations of the sex hormones in ER alpha-C451A precluded the interpretation of bone parameters that were thus analyzed on ovariectomized and supplemented or not with E2 (8 mu g/kg/d) to circumvent this bias. We found the beneficial action of E2 on femoral bone mineral density as well as in both cortical and cancellous bone was decreased in ER alpha-C451A mice compared with their wild-type littermates. Histological and biochemical approaches concurred with the results from bone marrow chimeras to demonstrate that ER alpha MISS signaling affects the osteoblast but not the osteoclast lineage in response to E2. Thus, in contrast to the uterine and endothelial effects of E2 that are specifically mediated by nuclear ER alpha and ER alpha MISS effects, respectively, bone protection is dependent on both, underlining the exquisite tissue-specific actions and interactions of membrane and nuclear ER alpha.
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| 2. |
- Adlanmerini, M., et al.
(författare)
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Mutation of Arginine 264 on ER alpha (Estrogen Receptor Alpha) Selectively Abrogates the Rapid Signaling of Estradiol in the Endothelium Without Altering Fertility
- 2020
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Ingår i: Arteriosclerosis, Thrombosis, and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 40:9, s. 2143-2158
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Tidskriftsartikel (refereegranskat)abstract
- Objective: ER alpha (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ER alpha palmitoylation site on some vasculoprotective actions of 17 beta-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ER alpha which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ER alpha). In contrast to theC451A-ER alpha, theR264A-ER alpha females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ER alpha protein abundance was normal, the well-described membrane ER alpha-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated inR264A-ER alpha mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ER alpha-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. Conclusions: These data underline the exquisite role of arginine 264 of ER alpha for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ER alpha signaling in vascular functions.
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