17 beta-estradiol impedes aortic root dilation and rupture in male Marfan mice.
Publication Year:
2023
PubMed ID:
37215011
Funding Grants:
Public Summary:
This study investigated whether 17β-estradiol (a form of estrogen) can protect against the aortic root dilation and rupture seen in male Marfan syndrome mice, a model of the inherited condition that weakens the aorta. Male Marfan mice typically develop larger and more rupture-prone aneurysms than females. When treated with 17β-estradiol, the mice showed slower aortic enlargement and better survival after being challenged with angiotensin II, which induces vessel stress. Gene expression analysis revealed that estradiol reduced activation of inflammatory pathways, especially those involving TNFα and NF-κB signaling, which drive a harmful switch in aortic smooth muscle cells from a contractile(stable) to an inflammatory (disease-promoting) state. In cultured cells, estradiol also blocked TNFα-induced inflammatory gene expression in an NF-κB–dependent manner. Overall, the results suggest that 17β-estradiol protects against aneurysm growth and rupture in Marfan syndrome by suppressing inflammation in aortic smooth muscle cells.
Scientific Abstract:
Marfan syndrome causes a hereditary form of thoracic aortic aneurysms with dilation of the aortic root. Human and animal models suggest a worse phenotype for males compared to females with respect to aneurysm size and risk of dissection. 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 aortic root size along with the risk of aortic rupture or dissection with the addition of angiotensin II was measured. Transcriptomic profiling was used to identify enriched pathways from 17 beta-estradiol treatment. Aortic smooth muscle cells were then treated with cytokines in order to validate the mechanism of 17 beta-estradiol protection. We show that 17 beta-estradiol decreased the size and rate of aortic root dilation and improved survival from rupture and dissection after treatment with angiotensin II. 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. These included many proteins known to play a role in the phenotypic shift of aortic smooth muscle cells from a contractile to a more inflammatory-like state such as Vcam-1, Mcp-1, Lgals3, Il-6, Il-1b, and C3. In addition, 17 beta-estradiol suppressed the induction of these TNFalpha induced genes in aortic smooth muscle cells in vitro and this effect appears to be NF-kappaB dependent. 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 and thus prevents the phenotypic switch of aortic smooth muscle cells from a contractile to an inflammatory state.