17 beta-Estradiol Impedes Aortic Root Dilation and Rupture in Male Marfan Mice.
Publication Year:
2023
PubMed ID:
37686377
Funding Grants:
Public Summary:
This study shows that 17β-estradiol (a form of estrogen) protects male Marfan syndrome mice from developing and dying from aortic root dilation and rupture, conditions that mimic human thoracic aortic aneurysms. Treated mice exhibited slower aortic growth, reduced inflammation, and improved survival. Gene expression analysis revealed that Marfan mice had strong activation of inflammatory pathways, particularly those driven by TNFα and NF-κB signaling, while estradiol treatment suppressed these inflammatory genes both in living mice and in cultured aortic smooth muscle cells. The findings suggest that 17β-estradiol prevents harmful vascular remodeling by blocking inflammation and maintaining smooth muscle cells in a healthy, contractile state—highlighting a potential protective mechanism underlying sex differences in Marfan-related aneurysm severity.
Scientific Abstract:
Marfan syndrome causes a hereditary form of thoracic aortic aneurysms with worse outcomes in male compared to female patients. In this study, we examine the effects of 17 beta-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 beta-estradiol, and the growth in the aortic root, along with the risk of aortic rupture, was measured. Transcriptomic profiling was used to identify enriched pathways from 17 beta-estradiol treatments. Aortic smooth muscle cells were then treated with cytokines to validate functional mechanisms. We show that 17 beta-estradiol decreased the size and rate of aortic root dilation and improved survival from rupture. The Marfan transcriptome was enriched in inflammatory genes, and the addition of 17 beta-estradiol modulated a set of genes that function through TNFalpha mediated NF-kappaB signaling. In addition, 17 beta-estradiol suppressed the induction of these TNFalpha induced genes in aortic smooth muscle cells in vitro in an NF-kappaB dependent manner, and 17 beta-estradiol decreased the formation of adventitial inflammatory foci in aortic roots in vivo. In conclusion, 17 beta-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNFalpha-NF-kappaB signaling.