Department of Neurosurgery, University of Florida, Gainesville, FL
Department of Neurosurgery, University of Florida, Gainesville, FL.
J Am Heart Assoc. 2018 Apr 13;7(8):e008863. doi: 10.1161/JAHA.118.008863.
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 (=0.03). Likewise, IL-17A inhibition was shown to prevent aneurysm formation by 42% (=0.02) and rupture by 34% (<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%; =0.04). Estradiol supplementation or IL-17A inhibition decreased the number of ruptures in estrogen-deficient mice (estradiol 6% versus 37%; =0.04; IL-17A inhibition 18% versus 47%; =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 (=0.003). E-cadherin inhibition reversed the protective effect of IL-17A inhibition and increased the rate of aneurysm formation (65% versus 28%; =0.04) and rupture (12% versus 0%; =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 (<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.
雌激素缺乏与脑动脉瘤的发展有关，但机制尚不清楚。我们通过研究雌激素缺乏与炎症因子之间的潜在联系，探讨了脑动脉瘤发展的途径。
首先，我们确定了白细胞介素-17A（IL-17A）的作用。我们进行了细胞因子筛选，结果表明 IL-17A 在小鼠和人类动脉瘤中表达显著（=0.03）。同样，IL-17A 抑制可使动脉瘤形成减少 42%（=0.02），破裂减少 34%（<0.05）。其次，我们发现雌激素缺乏会上调辅助性 T 细胞 17（Th17）细胞和 IL-17A，并促进动脉瘤破裂。雌激素缺乏的小鼠比对照组的小鼠有更多的破裂（47%比 7%；=0.04）。雌二醇补充或 IL-17A 抑制可减少雌激素缺乏小鼠的破裂数量（雌二醇 6%比 37%；=0.04；IL-17A 抑制 18%比 47%；=0.018）。第三，我们发现 IL-17A 阻断通过增加 E-钙黏蛋白表达来保护免受动脉瘤形成和破裂。IL-17 抑制的小鼠中 E-钙黏蛋白表达增加（=0.003）。E-钙黏蛋白抑制逆转了 IL-17A 抑制的保护作用，并增加了动脉瘤形成的速度（65%比 28%；=0.04）和破裂率（12%比 0%；=0.22）。然而，E-钙黏蛋白抑制本身并不能显著增加正常小鼠或雌激素缺乏小鼠的动脉瘤形成。在细胞迁移实验中，E-钙黏蛋白抑制促进了巨噬细胞穿过内皮细胞的浸润（<0.05），这可能是雌激素缺乏/IL-17/E-钙黏蛋白动脉瘤途径的机制。
我们的数据表明，雌激素缺乏通过上调 IL-17A 促进脑动脉瘤破裂，而下调 E-钙黏蛋白则促进巨噬细胞在动脉瘤血管壁中的浸润。
