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17 β-Estradiol Impedes Aortic Root Dilation and Rupture in Male Marfan Mice
Louis Saddic1, Sean Escopete2, Lior Zilberberg2
1Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
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 β-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 β-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 β-estradiol treatments. Aortic smooth muscle cells were then treated with cytokines to validate functional mechanisms. We show that 17 β-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 β-estradiol modulated a set of genes that function through TNFα mediated NF-κB signaling. In addition, 17 β-estradiol suppressed the induction of these TNFα induced genes in aortic smooth muscle cells in vitro in an NF-κB dependent manner, and 17 β-estradiol decreased the formation of adventitial inflammatory foci in aortic roots in vivo. In conclusion, 17 β-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNFα-NF-κB signaling.
Insights
17 beta-estradiol treatment reduced aortic root dilation and rupture risk in male Marfan mice. This hormone therapy offers potential for treating thoracic aortic aneurysms by inhibiting TNF-alpha-NF-kappaB inflammatory signaling.
Area of Science:
- Cardiovascular Biology
- Genetics
- Pharmacology
Background:
- Marfan syndrome is a genetic disorder leading to thoracic aortic aneurysms, with higher mortality in males.
- Aortic root dilation and rupture are critical complications of Marfan syndrome.
Purpose of the Study:
- To investigate the protective effects of 17 beta-estradiol on aortic dilation and rupture in a Marfan mouse model.
- To elucidate the molecular mechanisms underlying 17 beta-estradiol's action in Marfan syndrome.
Main Methods:
- Administration of 17 beta-estradiol to Marfan male mice.
- Measurement of aortic root growth and rupture incidence.
- Transcriptomic profiling to identify affected pathways.
- In vitro validation using aortic smooth muscle cells and cytokine treatment.
- In vivo assessment of aortic tissue inflammation.
Main Results:
- 17 beta-estradiol significantly decreased aortic root dilation and rupture risk, improving survival.
- Marfan mouse transcriptomes showed enrichment in inflammatory genes.
- 17 beta-estradiol modulated genes involved in TNF-alpha mediated NF-kappaB signaling.
- In vitro studies confirmed 17 beta-estradiol's suppression of TNF-alpha induced genes via NF-kappaB.
- Reduced adventitial inflammation was observed in treated aortas.
Conclusions:
- 17 beta-estradiol demonstrates a protective effect against aortic root dilation and rupture in male Marfan mice.
- The mechanism involves the inhibition of TNF-alpha-NF-kappaB inflammatory signaling pathway.
- This finding suggests a potential therapeutic role for 17 beta-estradiol in managing Marfan syndrome complications.
