{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T08:54:08Z","timestamp":1788598448033,"version":"build-2803163510"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T00:00:00Z","timestamp":1725148800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Mitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates that mutations of the human transcription factor\n                      <jats:italic toggle=\"yes\">FOXC1<\/jats:italic>\n                      are associated with MV defects, including MV regurgitation. In this study, we sought to determine whether murine\n                      <jats:italic toggle=\"yes\">Foxc1<\/jats:italic>\n                      and its closely related factor,\n                      <jats:italic toggle=\"yes\">Foxc2<\/jats:italic>\n                      , are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar ECM (extracellular matrix).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Adult mice carrying tamoxifen-inducible, vascular endothelial cell (EC), and lymphatic EC\u2013specific, compound\n                      <jats:italic toggle=\"yes\">Foxc1;Foxc2<\/jats:italic>\n                      mutations (ie, EC-\n                      <jats:italic toggle=\"yes\">Foxc<\/jats:italic>\n                      -DKO and lymphatic EC-\n                      <jats:italic toggle=\"yes\">Foxc<\/jats:italic>\n                      -DKO mice, respectively) were used to study the function of\n                      <jats:italic toggle=\"yes\">Foxc1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Foxc2<\/jats:italic>\n                      in the maintenance of MVs. The EC and lymphatic EC mutations of\n                      <jats:italic toggle=\"yes\">Foxc1\/c2<\/jats:italic>\n                      were induced at 7 to 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of these mutant mice were assessed via whole-mount immunostaining, immunohistochemistry\/RNAscope, Movat pentachrome\/Masson Trichrome staining, and Evans blue injection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      EC deletions of\n                      <jats:italic toggle=\"yes\">Foxc1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Foxc2<\/jats:italic>\n                      in mice resulted in abnormally extended and thicker MVs by causing defects in the regulation of ECM organization with increased proteoglycan and decreased collagen. Notably, reticular adherens junctions were found in VECs of control MV leaflets, and these reticular structures were severely disrupted in EC-\n                      <jats:italic toggle=\"yes\">Foxc<\/jats:italic>\n                      -DKO mice. PROX1 (prospero homeobox protein 1), a key regulator in a subset of VECs on the fibrosa side of MVs, was downregulated in EC-\n                      <jats:italic toggle=\"yes\">Foxc1\/c2<\/jats:italic>\n                      mutant VECs. Furthermore, we determined the precise location of lymphatic vessels in murine MVs, and these lymphatic vessels were aberrantly expanded and dysfunctional in EC-\n                      <jats:italic toggle=\"yes\">Foxc1\/c2<\/jats:italic>\n                      mutant MVs. Lymphatic EC deletion of\n                      <jats:italic toggle=\"yes\">Foxc1\/c2<\/jats:italic>\n                      also resulted in similar structural\/ECM abnormalities as seen in EC-\n                      <jats:italic toggle=\"yes\">Foxc1\/c2<\/jats:italic>\n                      mutant MVs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our results indicate that\n                      <jats:italic toggle=\"yes\">Foxc1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Foxc2<\/jats:italic>\n                      are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessel formation\/function to prevent myxomatous MV degeneration.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.124.320316","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T05:01:02Z","timestamp":1720674062000},"page":"1944-1959","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["FOXC1 and FOXC2 Ablation Causes Abnormal Valvular Endothelial Cell Junctions and Lymphatic Vessel Formation in Myxomatous Mitral Valve Degeneration"],"prefix":"10.1161","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1450-8396","authenticated-orcid":true,"given":"Can","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Medicine, Feinberg Cardiovascular and Renal Research Institute (C.T., S.K., Y.D., T.L., T.K.), Feinberg School of Medicine, Northwestern University, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7045-0846","authenticated-orcid":true,"given":"Zhi-Dong","family":"Ge","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Surgery, and Pathology, Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children\u2019s Research Institute, Ann &amp; Robert H. 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