Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin‐17A Which Downregulates E‐Cadherin. Issue 8 (13th April 2018)

• Record Type: Journal Article
• Authors: Hoh, Brian L.; Rojas, Kelley; Lin, Li; Fazal, Hanain Z.; Hourani, Siham; Nowicki, Kamil W.; Schneider, Matheus B.; Hosaka, Koji
• Is Part Of: Journal of the American Heart Association. Volume 7:Issue 8(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-04-13
• Subjects: aneurysm -- e‐cadherin -- estrogen -- IL‐17 -- macrophage; Heart -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Periodicals; Cerebrovascular disease -- Periodicals; Cardiology -- Periodicals; 616.1
• DOI: 10.1161/JAHA.118.008863
• Languages: English
• ISSNs: 2047-9980

Abstract

Abstract : Background: Estrogen deficiency is associated with the development of cerebral aneurysms; however, the mechanism remains unknown. We explored the pathway of cerebral aneurysm development by investigating the potential link between estrogen deficiency and inflammatory factors. Methods and Results: First, we established the role of interleukin‐17 (IL‐17)A. We performed a cytokine screen demonstrating that IL‐17A is significantly expressed in mouse and human aneurysms ( P =0.03). Likewise, IL‐17A inhibition was shown to prevent aneurysm formation by 42% ( P =0.02) and rupture by 34% ( P <0.05). Second, we found that estrogen deficiency upregulates T helper 17 cells and IL‐17A and promotes aneurysm rupture. Estrogen‐deficient mice had more ruptures than control mice (47% versus 7%; P =0.04). Estradiol supplementation or IL‐17A inhibition decreased the number of ruptures in estrogen‐deficient mice (estradiol 6% versus 37%; P =0.04; IL‐17A inhibition 18% versus 47%; P =0.018). Third, we found that IL‐17A‐blockade protects against aneurysm formation and rupture by increased E‐cadherin expression. IL‐17‐inhibited mice had increased E‐cadherin expression ( P =0.003). E‐cadherin inhibition reversed the protective effect of IL‐17A inhibition and increased the rate of aneurysm formation (65% versus 28%; P =0.04) and rupture (12% versus 0%; P =0.22). However, E‐cadherin inhibition alone does not significantly increase aneurysm formation in normal mice or in estrogen‐deficient mice. In cell migration assays, E‐cadherin inhibition promoted macrophage infiltration across endothelial cells ( P <0.05), which may be the mechanism for the estrogen deficiency/IL‐17/E‐cadherin aneurysm pathway. Conclusions: Our data suggest that estrogen deficiency promotes cerebral aneurysm rupture by upregulating IL‐17A, which downregulates E‐cadherin, encouraging macrophage infiltration in the aneurysm vessel wall.