{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T07:14:18Z","timestamp":1791616458026,"version":"4.3.4"},"reference-count":86,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,2,15]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Aortic valve stenosis is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain underexplored.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Hydrogel biomaterials were designed to recapitulate key aspects of the valve tissue microenvironment and to serve as a culture platform for sex-specific valvular interstitial cells (VICs; precursors to profibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA sequencing was used to define pathways involved in driving sex-dependent activation. Interventions with small molecule inhibitors and siRNA transfections were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker \u03b1-smooth muscle actin compared with male leaflets. When isolated and cultured, female porcine and human VICs had higher levels of basal \u03b1-smooth muscle actin stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than in male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase signaling as a potential driver of this sex-dependent myofibroblast activation. Furthermore, we found that genes that escape X-chromosome inactivation such as\n              <jats:italic>BMX<\/jats:italic>\n              and\n              <jats:italic>STS<\/jats:italic>\n              (encoding for Bmx nonreceptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation through Rho-associated protein kinase signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation through Rho-associated protein kinase signaling.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Together, in vivo and in vitro results confirm sex dependencies in myofibroblast activation pathways and implicate genes that escape X-chromosome inactivation in regulating sex differences in myofibroblast activation and subsequent aortic valve stenosis progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of aortic valve stenosis and to help guide sex-based precision therapies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.121.054108","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T10:00:20Z","timestamp":1641808820000},"page":"513-530","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":89,"title":["Genes That Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts"],"prefix":"10.1161","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4449-9806","authenticated-orcid":true,"given":"Brian A.","family":"Aguado","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering (B.A.A., J.C.G., B.J.V., A.G.R., K.S.A.), University of Colorado, Boulder."},{"name":"BioFrontiers Institute (B.A.A., J.C.G., M.E.S., D.B., A.G.R., L.A.L., K.S.A.), University of Colorado, Boulder."},{"name":"Department of Bioengineering, University of California, San Diego, La Jolla (B.A.A., B.J.V.)."},{"name":"Sanford Consortium for Regenerative Medicine, La Jolla, CA (B.A.A., B.J.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cierra J.","family":"Walker","sequence":"additional","affiliation":[{"name":"Materials Science and Engineering Program (C.J.W., M.E.S., K.S.A.), University of Colorado, Boulder."},{"name":"Department of Biochemistry (C.J.W., D.B.), University of Colorado, Boulder."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph C.","family":"Grim","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering (B.A.A., J.C.G., B.J.V., A.G.R., K.S.A.), University of Colorado, Boulder."},{"name":"BioFrontiers Institute (B.A.A., J.C.G., M.E.S., D.B., A.G.R., L.A.L., K.S.A.), University of Colorado, 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B.J.V., A.G.R., K.S.A.), University of Colorado, Boulder."},{"name":"Department of Bioengineering, University of California, San Diego, La Jolla (B.A.A., B.J.V.)."},{"name":"Sanford Consortium for Regenerative Medicine, La Jolla, CA (B.A.A., B.J.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Gonzalez","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering (B.A.A., J.C.G., B.J.V., A.G.R., K.S.A.), University of Colorado, Boulder."},{"name":"BioFrontiers Institute (B.A.A., J.C.G., M.E.S., D.B., A.G.R., L.A.L., K.S.A.), University of Colorado, Boulder."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A.","family":"Schwisow","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora (J.A.S., 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