{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:11:03Z","timestamp":1791360663647,"version":"4.3.1"},"reference-count":57,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Male sex and aging are risk factors for fibro-calcific aortic valve disease (FCAVD), indicating an understudied influence of sex hormones. Valvular interstitial cells (VICs) from female and male donors were isolated and exposed to pro-calcifying medium (PM), and the expression of matrix gla protein (MGP), fibronectin (FN1) and bone morphogenic protein 2 (BMP2) was analyzed. The effect of sex hormones on hydroxyapatite (HA) deposition by VICs was also analyzed. Exposure to PM increased MGP gene expression in male (n = 5, +5.8-fold, p = 0.031), and female VICs (n = 6, +4.9-fold, p = 0.004). In female VICs a +3.5-fold MGP increase accompanied the transition from the fibrotic to the calcific phase (p = 0.022 vs. males) while in male VICs the increase was delayed to the calcific phase. Female VICs upregulated FN1 (+1.8-fold, p = 0.003), while male VICs upregulated BMP2 (+3.7-fold, p = 0.05). 5\u03b1-dihydrotestosterone increased HA deposition +6.3-fold in male and +5.2-fold in female VICs (p \u2264 0.001 and p &lt; 0.04, respectively). It further decreased BMP2 (p &lt; 0.001) in male VICs and increased MGP in female VICs (p = 0.087). Female VICs decreased HA deposition when exposed to progesterone (\u22122.4-fold, p = 0.037 vs. PM) and estrogen (\u22122.0-fold, p = 0.072). In summary, VICs show donor-sex-specific gene expression which is modifiable by 5\u03b1-dihydrotestosterone. This needs to be considered when designing in vitro regulatory studies.<\/jats:p>","DOI":"10.3390\/ijms262110517","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T17:38:22Z","timestamp":1761759502000},"page":"10517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hormonal and Sex-Specific Regulation of Key Players in Fibro-Calcific Aortic Valve Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1547-2651","authenticated-orcid":false,"given":"Katherina","family":"Neussl","sequence":"first","affiliation":[{"name":"Department of Cardiology, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0169-998X","authenticated-orcid":false,"given":"Holger","family":"Thiele","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Schlotter","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany"},{"name":"Department of Cardiology, University Medical Center, Johannes Gutenberg University Mainz, German Center for Cardiovascular Research\u2014Partner Site Rhine-Main, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1046-1364","authenticated-orcid":false,"given":"Michael A.","family":"Borger","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0799-4725","authenticated-orcid":false,"given":"Petra","family":"B\u00fcttner","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"B\u00f6ttner","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.jacc.2008.05.043","article-title":"Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans","volume":"52","author":"Miller","year":"2008","journal-title":"J. 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