The Activation Function-1 of Estrogen Receptor Α Prevents Arterial Neointima Development Through a Direct Effect on Smooth Muscle Cells
Rationale: Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor alpha (ERα) via two activation functions, AF1 and AF2, and can also activate membrane ERα. The role of E2 on the endothelium relies on membrane ERα activation, but the molecular mechanisms of its action on vascular smooth muscle cells (VSMC) are not fully understood.
Objective: The aim of this study was to determine which cellular target and which ERα 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 VSMC-specific actions of E2. The molecular mechanisms underlying the role of E2 were further characterized using both selective ERα agonists and transgenic mice in which the ERαAF1 function had been specifically invalidated. We found that: 1) The selective inactivation of ERα in VSMC abrogates the neointimal hyperplasia protection induced by E2, whereas inactivation of endothelial and hematopoietic ERα has no effect; 2) The selective activation of membrane ERα does not prevent neointimal hyperplasia; 3) ERαAF1 is necessary and sufficient to inhibit post-injury VSMC proliferation.
Conclusions: Altogether, ERαAF1-mediated nuclear action is both necessary and sufficient to inhibit post-injury arterial VSMC proliferation, whereas membrane ERα largely regulates the endothelial functions of E2. This highlights the exquisite cell/tissue-specific actions of the ERα subfunctions, and helps to delineate the spectrum of action of selective ER modulators.
- Received March 9, 2015.
- Revision received August 24, 2015.
- Accepted August 27, 2015.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.