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A small fraction of MVD is syndromic and arises in association with matrix protein defects such as those in Marfan syndrome, but most MVD is acquired later in life through an undefined pathogenesis. The KLF2\/4 transcription factors mediate endothelial fluid shear responses, including those required to create cardiac valves during embryonic development. Here we test the role of hemodynamic shear forces and downstream endothelial KLF2\/4 in mature cardiac valves. We find that loss of hemodynamic forces in heterotopically transplanted hearts or genetic deletion of KLF2\/4 in cardiac valve endothelium confers valve cell proliferation and matrix deposition associated with valve thickening, findings also observed in mice expressing the mutant fibrillin-1 protein known to cause human MVD. Transcriptomic and histologic analysis reveals increased monocyte recruitment and TGF-\u03b2 signaling in both fibrillin-1\u2013mutant valves and valves lacking hemodynamic forces or endothelial KLF2\/4 function, but only loss of TGF-\u03b2\/SMAD signaling rescued myxomatous changes. We observed reduced KLF2\/4 expression and augmented SMAD signaling in human MVD. These studies identify hemodynamic activation of endothelial KLF2\/4 as an environmental homeostatic regulator of cardiac valves and suggest that non-syndromic MVD may arise in association with disturbed blood flow across the aging valve.<\/jats:p>","DOI":"10.1172\/jci186593","type":"journal-article","created":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T14:00:37Z","timestamp":1749996037000},"source":"Crossref","is-referenced-by-count":9,"title":["Hemodynamic forces prevent myxomatous valve disease in mice through KLF2\/4 signaling"],"prefix":"10.1172","volume":"135","author":[{"given":"Jesse A.","family":"Pace","sequence":"first","affiliation":[{"name":"Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Goddard","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Department of 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