| First Author | Smirnova NF | Year | 2015 |
| Journal | Circ Res | Volume | 117 |
| Issue | 9 | Pages | 770-8 |
| PubMed ID | 26316608 | Mgi Jnum | J:248704 |
| Mgi Id | MGI:6098988 | Doi | 10.1161/CIRCRESAHA.115.306416 |
| Citation | Smirnova NF, et al. (2015) The Activation Function-1 of Estrogen Receptor Alpha Prevents Arterial Neointima Development Through a Direct Effect on Smooth Muscle Cells. Circ Res 117(9):770-8 |
| abstractText | RATIONALE: 17beta-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor alpha (ERalpha) via 2 activation functions, AF1 and AF2, and can also activate membrane ERalpha. The role of E2 on the endothelium relies on membrane ERalpha activation, but the molecular mechanisms of its action on vascular smooth muscle cells (VSMCs) are not fully understood. OBJECTIVE: The aim of this study was to determine which cellular target and which ERalpha subfunction are involved in the preventive action of E2 on neointimal hyperplasia. METHODS AND RESULTS: To trigger neointimal hyperplasia of VSMC, we used a mouse model of femoral arterial injury. Cre-Lox models were used to distinguish between the endothelial- and the VSMC-specific actions of E2. The molecular mechanisms underlying the role of E2 were further characterized using both selective ERalpha agonists and transgenic mice in which the ERalphaAF1 function had been specifically invalidated. We found that (1) the selective inactivation of ERalpha in VSMC abrogates the neointimal hyperplasia protection induced by E2, whereas inactivation of endothelial and hematopoietic ERalpha has no effect; (2) the selective activation of membrane ERalpha does not prevent neointimal hyperplasia; and (3) ERalphaAF1 is necessary and sufficient to inhibit postinjury VSMC proliferation. CONCLUSIONS: Altogether, ERalphaAF1-mediated nuclear action is both necessary and sufficient to inhibit postinjury arterial VSMC proliferation, whereas membrane ERalpha largely regulates the endothelial functions of E2. This highlights the exquisite cell/tissue-specific actions of the ERalpha subfunctions and helps to delineate the spectrum of action of selective ER modulators. |
