RESUMO
BACKGROUND: 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 FOXC1 are associated with MV defects, including MV regurgitation. In this study, we sought to determine whether murine Foxc1 and its closely related factor, Foxc2, are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar ECM (extracellular matrix). METHODS: Adult mice carrying tamoxifen-inducible, vascular endothelial cell (EC), and lymphatic EC-specific, compound Foxc1;Foxc2 mutations (ie, EC-Foxc-DKO and lymphatic EC-Foxc-DKO mice, respectively) were used to study the function of Foxc1 and Foxc2 in the maintenance of MVs. The EC and lymphatic EC mutations of Foxc1/c2 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. RESULTS: EC deletions of Foxc1 and Foxc2 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-Foxc-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-Foxc1/c2 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-Foxc1/c2 mutant MVs. Lymphatic EC deletion of Foxc1/c2 also resulted in similar structural/ECM abnormalities as seen in EC-Foxc1/c2 mutant MVs. CONCLUSIONS: Our results indicate that Foxc1 and Foxc2 are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessel formation/function to prevent myxomatous MV degeneration.
Assuntos
Modelos Animais de Doenças , Células Endoteliais , Fatores de Transcrição Forkhead , Linfangiogênese , Vasos Linfáticos , Camundongos Knockout , Animais , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Valva Mitral/metabolismo , Valva Mitral/patologia , Mutação , Camundongos , Junções Intercelulares/metabolismo , Junções Intercelulares/patologia , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Doenças das Valvas Cardíacas/genética , Fenótipo , Camundongos Endogâmicos C57BL , Prolapso da Valva Mitral/metabolismo , Prolapso da Valva Mitral/genética , Prolapso da Valva Mitral/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologiaRESUMO
Estudos sobre hipermobilidade têm despertado grande interesse, nas últimas décadas, por estarem associados a disfunções músculo-esqueléticas, bem como a anormalidades em vários sistemas orgânicos - como, por exemplo, o prolapso da valva mitral. Neste contexto, buscou-se agrupar e atualizar os conhecimentos da relação entre a hipermobilidade articular e o prolapso da valva mitral. Segundo a literatura, estudos mostram que alterações genéticas na composição do colágeno parecem ser a principal causa desta relação.
Estudios sobre hipermovilidad han despertado gran interés en las últimas décadas por su relación con disfunciones musculoesqueléticas, así como con anormalidades en varios sistemas orgánicos - por ejemplo, el prolapso de la válvula mitral. Se buscó agrupar y actualizar, en ese contexto, los conocimientos de la relación entre la hipermovilidad articular y el prolapso de la válvula mitral. De acuerdo con la literatura, estudios indican que alteraciones genéticas en la composición del colágeno parecen ser la principal causa de esta relación.
Studies on hypermobility have aroused great interest in the last decades, as they are associated to musculoskeletal disorders, as well as abnormalities in several organic systems, such as the mitral valve prolapse. Therefore, in this study, data on the association between joint hypermobility and the mitral valve prolapse were investigated and reviewed. Studies in the literature have shown that genetic alterations in the collagen composition seem to be the main cause of this association.