Estrogen attenuates thoracic aortic aneurysm progression through reduced extracellular matrix remodeling and wall stiffening in a severe Marfan syndrome mouse model

Thoracic aortic aneurysm (TAA) is a life-threatening cardiovascular disease characterized by progressive aortic dilation and fatal dissection or rupture. Marfan syndrome (MFS)-associated TAA exhibits sexual dimorphism, suggesting a role for sex hormones. Although 17β-estradiol attenuates aortic root dilation in male MFS mice, the contribution of endogenous estrogen to sex-specific TAA progression and its effects on aortic wall extracellular matrix (ECM) remodeling and wall stiffness remains poorly understood. Using a severe MFS mouse model ( Fbn1 mgR/mgR ) with TAA formation and reduced lifespan, male mice received 17β-estradiol or placebo pellets and female mice underwent bilateral ovariectomy (OVX) or sham surgery, starting at one month of age. In vivo ascending thoracic aortic (ATA) geometry and wall stiffness were assessed by ultrasound imaging and ECM remodeling and α-SMA protein amount were evaluated by multiphoton imaging and immunofluorescence, respectively. 17β-estradiol-treated male and sham female mice exhibited slow ATA dilation, preserved wall stiffness, and prolonged survival, whereas placebo-treated male and OVX female mice showed fast ATA dilation, age-dependent wall stiffening, and reduced survival. Histological analysis demonstrated marked elastic fiber fragmentation in the ECM and loss of α-SMA amounts in placebo-treated male and OVX female mice, while 17β-estradiol-treated male and sham female mice displayed intact elastic fibers and preserved α-SMA expression. Overall, these findings demonstrate a protective role of estrogen in maintaining ECM integrity, aortic wall stiffness, and vascular smooth muscle cell phenotype, thereby attenuating ATA progression and improving long-term survival in MFS mice.