Lack of endothelial estrogen receptor alpha signaling exacerbates abdominal aortic aneurysm in male mice.

Abstract

Abdominal aortic aneurysm (AAA), a pathological dilatation of the abdominal aorta, is primarily driven by chronic inflammation of the aortic wall. Although estrogen is known to exert protective anti-inflammatory effects in AAA, the role of endothelial estrogen receptor alpha (ERα) signaling in AAA pathogenesis remains unclear. We investigated the vasoprotective role of endothelial ERα using endothelial cell (EC)-specific ERα knockout (eERαKO) mice subjected to a beta-aminopropionitrile plus angiotensin II model of AAA. eERα deficiency significantly accelerated AAA formation in male mice, evidenced by increased maximal aortic diameter, worsened medial elastin degradation, increased collagen deposition, and upregulated macrophage infiltration, whereas female mice were largely unaffected. Mechanistically, loss of endothelial ERα was associated with elevated endothelin-1 (ET-1) expression in aortic tissue. In vitro, pharmacological inhibition of ERα with methyl-piperidino-pyrazole increased endothelial ET-1 secretion and increased monocyte adhesion in EC-monocyte coculture assays. Collectively, these findings reveal that endothelial ERα constrains AAA development in male mice, possibly by suppressing ET-1-mediated endothelial activation and macrophage recruitment. This work highlights a protective role of endothelial ERα signaling in maintaining aortic structural integrity and preventing aneurysmal disease.NEW & NOTEWORTHY We identify an important role of endothelial estrogen receptor alpha (ERα) in a sex-dependent regulation of abdominal aortic aneurysm formation. Using mice with endothelial cell-specific deletion of ERα, we found that loss of endothelial ERα signaling exacerbates aneurysm development in male mice, associated with increased macrophage infiltration and elevated endothelin-1 expression. These findings reveal a previously unrecognized endothelial-specific mechanism by which estrogen signaling preserves aortic wall integrity and suppresses inflammatory vascular remodeling.