FOXC1 and FOXC2 Ablation Causes Abnormal Valvular Endothelial Cell Junctions and Lymphatic Vessel Formation in Myxomatous Mitral Valve Degeneration
Year: 2024
Type: article
Abstract: 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.
Authors: Can Tan, Zhi-Dong Ge, Shreya Kurup, Yaryna Dyakiv, Ting Liu, William A. Muller, Tsutomu Kume
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G1284175734, G1382277591, G1697802790, G317886719, G6544658276, Molecular mechanisms of Foxc-mediated angiogenesis, G9000046704, G9000243610, Novel ocular imaging and molecular analysis of anterior eye segment for glaucoma, Transendothelial Migration of Leukocytes: Developing New Paradigms in Health and Disease, The Robert H. Lurie Comprehensive Cancer Center, New roles of endothelial regrowth in ischemic tissue recovery and regeneration
OpenAlex ID: W4400557623