{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:05:44Z","timestamp":1768507544642,"version":"3.49.0"},"posted":{"date-parts":[[2023,8,30]]},"group-title":"Cell Biology","reference-count":35,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,8,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <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 mutations of the transcription factor\n                    <jats:italic>FOXC1<\/jats:italic>\n                    are associated with MV defects, including mitral valve regurgitation. In this study, we sought to determine whether murine\n                    <jats:italic>Foxc1<\/jats:italic>\n                    and its closely related factor,\n                    <jats:italic>Foxc2<\/jats:italic>\n                    , are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar extracellular matrix (ECM).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Adult mice carrying tamoxifen-inducible, endothelial cell (EC)-specific, compound\n                    <jats:italic>Foxc1;Foxc2<\/jats:italic>\n                    mutations (i.e., EC-\n                    <jats:italic>Foxc<\/jats:italic>\n                    -DKO mice) were used to study the function of\n                    <jats:italic>Foxc1<\/jats:italic>\n                    and\n                    <jats:italic>Foxc2<\/jats:italic>\n                    in the maintenance of mitral valves. The EC-mutations of\n                    <jats:italic>Foxc1\/c2<\/jats:italic>\n                    were induced at 7 \u2013 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of EC-\n                    <jats:italic>Foxc<\/jats:italic>\n                    -DKO mice were assessed via whole-mount immunostaining, immunohistochemistry, and Movat pentachrome\/Masson\u2019s Trichrome staining.\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>Foxc1<\/jats:italic>\n                    and\n                    <jats:italic>Foxc2<\/jats:italic>\n                    in mice resulted in abnormally extended and thicker mitral valves by causing defects in 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>Foxc1\/c2<\/jats:italic>\n                    mutant mice. PROX1, a key regulator in a subset of VECs on the fibrosa side of MVs, was downregulated in EC-\n                    <jats:italic>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 in EC-\n                    <jats:italic>Foxc1\/c2<\/jats:italic>\n                    mutant mitral valves.\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>Foxc1<\/jats:italic>\n                    and\n                    <jats:italic>Foxc2<\/jats:italic>\n                    are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessels to prevent myxomatous mitral valve degeneration.\n                  <\/jats:p>\n                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