| First Author | Adlanmerini M | Year | 2020 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 40 |
| Issue | 9 | Pages | 2143-2158 |
| PubMed ID | 32640903 | Mgi Jnum | J:302599 |
| Mgi Id | MGI:6508718 | Doi | 10.1161/ATVBAHA.120.314159 |
| Citation | Adlanmerini M, et al. (2020) Mutation of Arginine 264 on ERalpha (Estrogen Receptor Alpha) Selectively Abrogates the Rapid Signaling of Estradiol in the Endothelium Without Altering Fertility. Arterioscler Thromb Vasc Biol 40(9):2143-2158 |
| abstractText | OBJECTIVE: ERalpha (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 ERalpha palmitoylation site on some vasculoprotective actions of 17beta-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERalpha 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-ERalpha). In contrast to the C451A-ERalpha, the R264A-ERalpha females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERalpha protein abundance was normal, the well-described membrane ERalpha-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERalpha 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 ERalpha-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 ERalpha 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 ERalpha signaling in vascular functions. |
