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We examined nicotine\u2019s effects on angiotensin II (AngII)-induced AAAs in male and female low-density lipoprotein receptor-deficient (Ldlr-\/-) mice. Moreover, we defined effects of gonadectomy (GDX) of both sexes on nicotine-induced regulation of AAAs. Male and female Ldlr-\/- mice (8\u201312 weeks of age) were infused with AngII with or without nicotine. Mice underwent sham or GDX surgeries prior to infusions of AngII and nicotine. In males, one or both testes were removed. AAA incidence, size, severity, and serum indices of nicotine metabolism were quantified. Effects of testosterone or estrogen on abdominal aortic smooth muscle cells (SMCs) were assessed. Nicotine increased aortic rupture in males, with modest effects in females. GDX reduced AAA incidence in male mice but had modest effects in females. Serum ratios of trans-3-hydroxycotinine to cotinine, an index of nicotine metabolism, were higher in females and increased by GDX in both sexes. Co-infusion of nicotine with AngII increased matrix metalloproteinase 2 (MMP2) mRNA in abdominal aortas of males, but not females. Similarly, testosterone increased MMP2 mRNA in male, but not female abdominal aortic SMCs. Testosterone reduced markers of a contractile SMC phenotype in SMCs from males, with no effects of estrogen in females. In conclusion, nicotine augments AngII-induced AAAs to a greater extent in males, with sex differences related to influences of sex hormones on nicotine metabolism, aortic MMP2 expression, and markers of a contractile SMC phenotype.<\/jats:p>","DOI":"10.1042\/cs20255689","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T15:47:48Z","timestamp":1744213668000},"page":"411-429","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Nicotine promotes AngII-induced abdominal aortic aortopathies in female and male mice: role of sex hormones"],"prefix":"10.1042","volume":"139","author":[{"given":"Mark","family":"Ensor","sequence":"first","affiliation":[{"name":"1Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean E.","family":"Thatcher","sequence":"additional","affiliation":[{"name":"2Biomedical Education and Data Science, Temple University, Philadelphia, PA, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"McQuerry","sequence":"additional","affiliation":[{"name":"3Department of Biostatistics, University of Kentucky, Lexington, KY, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kory","family":"Heier","sequence":"additional","affiliation":[{"name":"3Department of Biostatistics, University of Kentucky, Lexington, KY, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba M.","family":"Ali","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, U.S.A."},{"name":"4Department of Pediatrics, University of Kentucky, Lexington, KY, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"English","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa A.","family":"Cassis","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5809-7909","authenticated-orcid":false,"given":"Yasir","family":"Alsiraj","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, U.S.A."},{"name":"4Department of Pediatrics, University of Kentucky, Lexington, KY, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"2025042515134080200_CS-2025-5689C1","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1586\/14779072.2015.1074861","article-title":"Understanding the pathogenesis of abdominal aortic aneurysms","volume":"13","author":"Kuivaniemi","year":"2015","journal-title":"Expert Rev. 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