Estrogen Inhibits the Phenotypic Switching of Vascular Smooth Muscle Cells through ER-α/CREB in Aortic Dissection

Objective: To examine the alterations in estrogen levels in patients with aortic dissection (AD) and its protective effect on AD patients through the inhibition of vascular smooth muscle cells (VSMCs) phenotypic switching via the ER-α/CREB pathway. Methods: Demographic data were collected to assess sex disparity in AD patients, and serum 17β-estradiol (E2) levels were measured using ELISA. Phenotypic switching markers were analyzed in aortic tissues from AD patients and controls. Bioinformatics analysis identified estrogen-related pathways, focusing on the ER-α/CREB axis, with expression levels confirmed via immunohistochemistry and Western blot. AD mouse models were developed in male and ovariectomized female mice, with the effects of E2 supplementation on AD progression and VSMCs phenotypic switching evaluated. An AD cellular model was also employed to verify these findings through targeted pathway inhibition. Results: AD prevalence was higher in males, with reduced serum E2 levels observed in both male and postmenopausal female patients. Ovariectomized female mice showed increased AD incidence, while E2 supplementation reduced AD progression by inhibiting the phenotypic switching of VSMCs. Downregulation of ER-α and p-CREB/CREB expression was observed in AD patients, and E2 enhanced ER-α expression and CREB phosphorylation, preventing VSMC phenotypic switching. E2 also promoted ER-α/CREB interaction, and silencing ER-α inhibited CREB phosphorylation, leading to increased VSMC phenotypic switching. Conclusions: Estrogen (E2) plays a crucial role in preventing AD by maintaining VSMCs synthetic phenotype through the ER-α/CREB signaling pathway, providing a protective effect against the development of AD.