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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.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>METHODS<\/jats:title>\n<jats:p>Ten-week-old female Sprague Dawley rats with and without oophorectomy were subjected to hemodynamic changes and hypertension (OVX<jats:sup>+<\/jats:sup>\/HT and OVX<jats:sup>\u2212<\/jats:sup>\/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.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>RESULTS<\/jats:title>\n<jats:p>In OVX<jats:sup>+<\/jats:sup>\/HT rats, the frequency of IA rupture was significantly higher than in OVX<jats:sup>\u2212<\/jats:sup>\/HT rats (p = 0.03). In the left posterior cerebral artery prone to rupture in OVX<jats:sup>+<\/jats:sup>\/HT rats, the levels of the mRNAs encoding <jats:italic>ER\u03b1<\/jats:italic> and<jats:italic> Sirt1<\/jats:italic>, but not of that encoding <jats:italic>ER\u03b2<\/jats:italic>, were decreased, and the levels of the mRNAs encoding <jats:italic>NLRP3<\/jats:italic>, interleukin-1\u03b2 (<jats:italic>IL-1\u03b2<\/jats:italic>), and matrix metalloproteinase 9 (<jats:italic>MMP-9<\/jats:italic>) 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 ER\u03b1 and Sirt1 and the accumulation of NLRP3 were counteracted by exposure to estradiol or to an ER\u03b1 agonist but not to an ER\u03b2 agonist.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>CONCLUSIONS<\/jats:title>\n<jats:p>To the authors\u2019 knowledge, this work represents the first demonstration that, in an aneurysm model under estrogen-deficient conditions, the depletion of ER\u03b1 and Sirt1 may contribute to activation of the NLRP3\/IL-1\u03b2\/MMP-9 pathway, facilitating the rupture of IAs in the estrogen-deficient rat IA rupture model.<\/jats:p>\n<\/jats:sec>","DOI":"10.3171\/2022.4.jns212945","type":"journal-article","created":{"date-parts":[[2022,5,28]],"date-time":"2022-05-28T05:05:46Z","timestamp":1653714346000},"page":"191-198","source":"Crossref","is-referenced-by-count":27,"title":["Activation of the NLRP3\/IL-1\u03b2\/MMP-9 pathway and intracranial aneurysm rupture associated with the depletion of ER\u03b1 and Sirt1 in oophorectomized rats"],"prefix":"10.3171","volume":"138","author":[{"given":"Tadashi","family":"Yamaguchi","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Shikata","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izumi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Shimada","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Yagi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiteru","family":"Tada","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Korai","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko T.","family":"Kitazato","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhisa","family":"Kanematsu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Takagi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"issue":"3","key":"b1","series-title":"JAMA Neurol","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1001\/jamaneurol.2018.4165","article-title":"Procedural clinical complications, case-fatality risks, and risk factors in endovascular and neurosurgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis","volume":"76","author":"Algra AM","year":"2019","unstructured":"Algra AM, Lindgren A, Vergouwen MDI,  Procedural clinical complications, case-fatality risks, and risk factors in endovascular and neurosurgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis. 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