Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin-17A Which Downregulates E-Cadherin.

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. 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. 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.