Yamaguchi Tadashi, Miyamoto Takeshi, Shikata Eiji, Yamaguchi Izumi, Shimada Kenji, Yagi Kenji, Tada Yoshiteru, Korai Masaaki, Kitazato Keiko T, Kanematsu Yasuhisa, Takagi Yasushi
J Neurosurg. 2022 May 20;138(1):191-198. doi: 10.3171/2022.4.JNS212945. Print 2023 Jan 1.
Subarachnoid hemorrhage (SAH) due to intracranial aneurysm (IA) rupture is often a devastating event. Since the incidence of SAH increases especially in menopause, it is crucial to clarify the detailed pathogenesis of these events. The activation of vascular nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes has been studied in ischemic stroke and cardiovascular disease. However, the role of NLRP3 in IA rupture still needs to be explained. The authors sought to test their hypothesis that, under estrogen-deficient conditions, activation of NLRP3 inflammasomes via downregulation of the estrogen receptor (ER) facilitates IA rupture.
Ten-week-old female Sprague Dawley rats with and without oophorectomy were subjected to hemodynamic changes and hypertension (OVX+/HT and OVX-/HT, respectively) and fed a high-salt diet. Separately, using human brain endothelial cells (HBECs) and human brain smooth muscle cells (HBSMCs), the authors tested the effect of NLRP3 under estrogen-free conditions and in the presence of estradiol or of ER agonists.
In OVX+/HT rats, the frequency of IA rupture was significantly higher than in OVX-/HT rats (p = 0.03). In the left posterior cerebral artery prone to rupture in OVX+/HT rats, the levels of the mRNAs encoding ERα and Sirt1, but not of that encoding ERβ, were decreased, and the levels of the mRNAs encoding NLRP3, interleukin-1β (IL-1β), and matrix metalloproteinase 9 (MMP-9) were elevated. Immunohistochemical analysis demonstrated that the expression profiles of these proteins correlated with their mRNA levels. Treatment with an ER modulator, bazedoxifene, normalized the expression profiles of these proteins and improved SAH-free survival. In HBECs and HBSMCs under estrogen-free conditions, the depletion of ERα and Sirt1 and the accumulation of NLRP3 were counteracted by exposure to estradiol or to an ERα agonist but not to an ERβ agonist.
To the authors' knowledge, this work represents the first demonstration that, in an aneurysm model under estrogen-deficient conditions, the depletion of ERα and Sirt1 may contribute to activation of the NLRP3/IL-1β/MMP-9 pathway, facilitating the rupture of IAs in the estrogen-deficient rat IA rupture model.
颅内动脉瘤（IA）破裂导致的蛛网膜下腔出血（SAH）通常是一种灾难性事件。由于SAH的发病率在绝经后尤其增加，阐明这些事件的详细发病机制至关重要。血管核苷酸结合寡聚化结构域样受体家族含pyrin结构域3（NLRP3）炎性小体的激活已在缺血性中风和心血管疾病中得到研究。然而，NLRP3在IA破裂中的作用仍有待阐明。作者试图验证他们的假设，即在雌激素缺乏的条件下，通过雌激素受体（ER）下调激活NLRP3炎性小体促进IA破裂。
对10周龄有或无卵巢切除术的雌性Sprague Dawley大鼠进行血流动力学改变和高血压处理（分别为OVX+/HT和OVX-/HT），并给予高盐饮食。另外，作者使用人脑内皮细胞（HBECs）和人脑平滑肌细胞（HBSMCs），测试了在无雌激素条件下以及存在雌二醇或ER激动剂时NLRP3的作用。
在OVX+/HT大鼠中，IA破裂的频率显著高于OVX-/HT大鼠（p = 0.03）。在OVX+/HT大鼠中易于破裂的左大脑后动脉中，编码ERα和Sirt1的mRNA水平降低，但编码ERβ的mRNA水平未降低，而编码NLRP3、白细胞介素-1β（IL-1β）和基质金属蛋白酶9（MMP-9）的mRNA水平升高。免疫组织化学分析表明这些蛋白质的表达谱与其mRNA水平相关。用ER调节剂巴多昔芬治疗可使这些蛋白质的表达谱正常化，并改善无SAH的生存率。在无雌激素条件下的HBECs和HBSMCs中，暴露于雌二醇或ERα激动剂可抵消ERα和Sirt1的耗竭以及NLRP3的积累，但暴露于ERβ激动剂则不能。
据作者所知，这项工作首次证明，在雌激素缺乏条件下的动脉瘤模型中，ERα和Sirt1的耗竭可能导致NLRP3/IL-1β/MMP-9途径的激活，促进雌激素缺乏大鼠IA破裂模型中IA的破裂。
