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FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration

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 mutations of the transcription factor FOXC1 are associated with MV defects, including mitral valve regurgitation. In t...

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Autores principales: Tan, Can, Kurup, Shreya, Dyakiv, Yaryna, Kume, Tsutomu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491158/
https://www.ncbi.nlm.nih.gov/pubmed/37693499
http://dx.doi.org/10.1101/2023.08.30.555455
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author Tan, Can
Kurup, Shreya
Dyakiv, Yaryna
Kume, Tsutomu
author_facet Tan, Can
Kurup, Shreya
Dyakiv, Yaryna
Kume, Tsutomu
author_sort Tan, Can
collection PubMed
description 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 mutations of the transcription factor FOXC1 are associated with MV defects, including mitral valve 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 extracellular matrix (ECM). METHODS: Adult mice carrying tamoxifen-inducible, endothelial cell (EC)-specific, compound Foxc1;Foxc2 mutations (i.e., EC-Foxc-DKO mice) were used to study the function of Foxc1 and Foxc2 in the maintenance of mitral valves. The EC-mutations of Foxc1/c2 were induced at 7 – 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of EC-Foxc-DKO mice were assessed via whole-mount immunostaining, immunohistochemistry, and Movat pentachrome/Masson’s Trichrome staining. RESULTS: EC-deletions of Foxc1 and Foxc2 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-Foxc1/c2 mutant mice. PROX1, 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 in EC-Foxc1/c2 mutant mitral valves. CONCLUSIONS: Our results indicate that Foxc1 and Foxc2 are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessels to prevent myxomatous mitral valve degeneration.
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spelling pubmed-104911582023-09-09 FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration Tan, Can Kurup, Shreya Dyakiv, Yaryna Kume, Tsutomu bioRxiv Article 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 mutations of the transcription factor FOXC1 are associated with MV defects, including mitral valve 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 extracellular matrix (ECM). METHODS: Adult mice carrying tamoxifen-inducible, endothelial cell (EC)-specific, compound Foxc1;Foxc2 mutations (i.e., EC-Foxc-DKO mice) were used to study the function of Foxc1 and Foxc2 in the maintenance of mitral valves. The EC-mutations of Foxc1/c2 were induced at 7 – 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of EC-Foxc-DKO mice were assessed via whole-mount immunostaining, immunohistochemistry, and Movat pentachrome/Masson’s Trichrome staining. RESULTS: EC-deletions of Foxc1 and Foxc2 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-Foxc1/c2 mutant mice. PROX1, 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 in EC-Foxc1/c2 mutant mitral valves. CONCLUSIONS: Our results indicate that Foxc1 and Foxc2 are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessels to prevent myxomatous mitral valve degeneration. Cold Spring Harbor Laboratory 2023-08-30 /pmc/articles/PMC10491158/ /pubmed/37693499 http://dx.doi.org/10.1101/2023.08.30.555455 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Tan, Can
Kurup, Shreya
Dyakiv, Yaryna
Kume, Tsutomu
FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration
title FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration
title_full FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration
title_fullStr FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration
title_full_unstemmed FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration
title_short FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration
title_sort foxc1 and foxc2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491158/
https://www.ncbi.nlm.nih.gov/pubmed/37693499
http://dx.doi.org/10.1101/2023.08.30.555455
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