{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T05:31:42Z","timestamp":1785735102718,"version":"3.56.0"},"reference-count":81,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":62,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01HL159976"],"award-info":[{"award-number":["R01HL159976"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["R01EY034740"],"award-info":[{"award-number":["R01EY034740"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:p>\n                    Enhanced TGF-\u03b2 signaling caused by mutations in Fibrillin-1 (FBN1) in patients with Marfan syndrome (MFS) leads to myxomatous degeneration of the mitral valve (MDMV). MDMV can result in mitral valve prolapse, severe regurgitation, and sudden cardiac death. However, it remains unknown whether lymphatic vessel (LV) dysfunction contributes to MDMV development in MFS. Here, we show that lymphangiogenesis in murine mitral valves (MVs) begins postnatally. However, this process is inhibited in a mouse MFS model,\n                    <jats:italic>Fbn1<\/jats:italic>\n                    mutant (\n                    <jats:italic>\n                      Fbn1\n                      <jats:sup>C1039G\/+<\/jats:sup>\n                    <\/jats:italic>\n                    ) mice, accompanied by disrupted lymphatic cell-cell junctions, impaired lymphatic drainage, and an abnormally widespread distribution of MHCII\n                    <jats:sup>+<\/jats:sup>\n                    infiltrating macrophages. Treatment of\n                    <jats:italic>Fbn1<\/jats:italic>\n                    mutant mice with VEGF-C156S, a selective VEGFR3 agonist, stimulates the ERK and Akt pathways, increases LV density in MVs, and ameliorates MDMV.\n                    <jats:italic>Fbn1<\/jats:italic>\n                    mutant MVs display disorganized valvular endothelial cells (VECs) and decreased expression of the antiinflammatory modulator\n                    <jats:italic>Zfp36<\/jats:italic>\n                    (zinc finger protein 36) in VECs and immune cells. Treatment with FTY720 (fingolimod), a ZFP36 activator and S1P antagonist, rescues MDMV phenotypes in\n                    <jats:italic>Fbn1<\/jats:italic>\n                    mutant mice by reducing immune cell infiltration and restoring lymphatic cell junctions and drainage. These findings suggest that the\n                    <jats:italic>Fbn1<\/jats:italic>\n                    mutation causes LV hypoplasia and defective lymphatic drainage in MVs, driven in part by proinflammatory VECs, leading to MFS-related MDMV.\n                  <\/jats:p>\n                  <jats:p>Lymphatic dysfunction, linked to inflammation, contributes to mitral valve disease in a mouse model of Marfan syndrome. Treatments that restore lymphatic function reverse valve abnormalities.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1172\/jci195507","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T14:39:35Z","timestamp":1781188775000},"source":"Crossref","is-referenced-by-count":1,"title":["Lymphatic dysfunction and ZFP36 deficiency contribute to myxomatous valve degeneration in Marfan syndrome mice"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1450-8396","authenticated-orcid":true,"given":"Can","family":"Tan","sequence":"first","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyou","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Dermatology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya","family":"Kurup","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianpeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery\/Canning Thoracic Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Dong","family":"Ge","sequence":"additional","affiliation":[{"name":"Cardiovascular-Thoracic Surgery and The Heart Center, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. 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