{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T01:12:45Z","timestamp":1767834765887,"version":"3.49.0"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T00:00:00Z","timestamp":1719878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Bicuspid aortic valves (BAV) are frequently associated with ascending aortic aneurysms. The etiology is incompletely understood, but genetic factors, in addition to flow perturbations, are likely involved. Since loss of contractility and elaboration of extracellular matrix in the vessel wall are features of BAV-associated aortopathy, phenotypic modulation of smooth muscle cells (SMCs) may play a role.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Ascending aortic tissue was collected intra-operatively from 25 individuals with normal (i.e., tricuspid) aortic valves (TAV) and from 25 individuals with BAVs. For both TAV and BAV, 10 patients had non-dilated (ND) and 15 patients had dilated (D) aortas. SMCs were isolated and cultured from a subset of patients from each group. Aortic tissue and SMCs were fluorescently immunolabeled for SMC phenotypic markers (i.e., alpha-smooth muscle actin (ASMA, contractile), vimentin (synthetic) and p16<jats:sup>INK4a<\/jats:sup> and p21<jats:sup>Cip1<\/jats:sup> (senescence). SMCs were also analyzed for replicative senescence in culture.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>In normal-sized and dilated BAV aortas, SMCs switched from the contractile state to either synthetic or senescent phenotypes, as observed by loss of ASMA (ND: <jats:italic>P<\/jats:italic> = 0.001, D: <jats:italic>P<\/jats:italic> = 0.002) and associated increases in vimentin (ND: <jats:italic>P<\/jats:italic> = 0.03, D: <jats:italic>P<\/jats:italic> = 0.004) or p16\/p21 (ND: <jats:italic>P<\/jats:italic> = 0.03, D: <jats:italic>P<\/jats:italic>&lt;0.0001) compared to TAV. Dilatation of the aorta exacerbated SMC phenotypic switching in both BAV and TAV aortas (all <jats:italic>P<\/jats:italic>&lt;0.05). In SMCs cultured from normal and dilated aortas, those isolated from BAV reached replicative senescence faster than those from TAV aortas (all <jats:italic>P<\/jats:italic> = 0.02). Furthermore, there was a stark inverse correlation between ASMA and cell passage number in BAV SMCs (ND: <jats:italic>P<\/jats:italic> = 0.0006, D: <jats:italic>P<\/jats:italic> = 0.01), but not in TAV SMCs (ND: <jats:italic>P<\/jats:italic> = 0.93, D: <jats:italic>P<\/jats:italic> = 0.20).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The findings of this study provide direct evidence from cell culture studies implying that SMCs switch from the contractile state to either synthetic or senescent phenotypes in the non-dilated BAV aorta. In cultured SMCs from both non-dilated and dilated aortas, we found that this process may precede dilatation and accompany aneurysm development in BAV. Our findings suggest that therapeutically targeting SMC phenotypic modulation in BAV patients may be a viable option to prevent or delay ascending aortic aneurysm formation.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0306515","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T19:20:51Z","timestamp":1719948051000},"page":"e0306515","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Smooth muscle cell phenotypic switching occurs independent of aortic dilation in bicuspid aortic valve-associated ascending aortas"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7520-9509","authenticated-orcid":true,"given":"Brittany","family":"Balint","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00e9s Garc\u00eda Lascurain","family":"Bernstorff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanja","family":"Schwab","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans-Joachim","family":"Sch\u00e4fers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"key":"pone.0306515.ref001","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1161\/CIRCULATIONAHA.113.007851","article-title":"Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon)","volume":"129","author":"HI Michelena","year":"2014","journal-title":"Circulation"},{"key":"pone.0306515.ref002","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1056\/NEJMra1207059","article-title":"Aortic dilatation in patients with bicuspid aortic valve","volume":"370","author":"S Verma","year":"2014","journal-title":"N Engl J Med"},{"key":"pone.0306515.ref003","doi-asserted-by":"crossref","first-page":"e016471","DOI":"10.1161\/JAHA.120.016471","article-title":"Dysregulation of Endothelial Nitric Oxide Synthase Does Not Depend on Hemodynamic Alterations in Bicuspid Aortic Valve Aortopathy.","volume":"9","author":"S Gauer","year":"2020","journal-title":"J Am Heart Assoc"},{"key":"pone.0306515.ref004","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.jacc.2015.06.1310","article-title":"Valve-Related Hemodynamics Mediate Human Bicuspid Aortopathy: Insights From Wall Shear Stress Mapping","volume":"66","author":"DG Guzzardi","year":"2015","journal-title":"J Am Coll Cardiol"},{"key":"pone.0306515.ref005","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1161\/CIRCULATIONAHA.113.003026","article-title":"Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy","volume":"129","author":"R Mahadevia","year":"2014","journal-title":"Circulation"},{"key":"pone.0306515.ref006","doi-asserted-by":"crossref","first-page":"928362","DOI":"10.3389\/fcvm.2022.928362","article-title":"Experimental evidence of the genetic hypothesis on the etiology of bicuspid aortic valve aortopathy in the hamster model.","volume":"9","author":"MT Soto-Navarrete","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"pone.0306515.ref007","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ebiom.2019.04.060","article-title":"Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve disease.","volume":"43","author":"B Balint","year":"2019","journal-title":"EBioMedicine"},{"key":"pone.0306515.ref008","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S0022-5223(03)00398-2","article-title":"Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation","volume":"126","author":"PW Fedak","year":"2003","journal-title":"J Thorac Cardiovasc Surg"},{"key":"pone.0306515.ref009","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.carpath.2016.03.002","article-title":"Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association For European Cardiovascular Pathology: II. 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