Stress-induced remodelling of the mitral valve: a model for leaflet thickening and superimposed tissue formation in mitral valve disease
| Autor: | Marie-José Goumans, Yasmine L. Hiemstra, Victoria Delgado, Laura Paardekooper, Boudewijn P.T. Kruithof, Meindert Palmen, Robert J.M. Klautz, Nina Ajmone Marsan |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Time Factors Mechanical stress Physiology Valve remodelling Mice Transgenic Smad Proteins 030204 cardiovascular system & hematology Mechanotransduction Cellular Myxomatous degeneration Tissue Culture Techniques Extracellular matrix 03 medical and health sciences 0302 clinical medicine Cell Movement Transforming Growth Factor beta Physiology (medical) Mitral valve medicine Animals Humans Mitral valve prolapse Phosphorylation Aged Superimposed tissue biology Cardiac cycle Chemistry Macrophages Hemodynamics Endothelial Cells Mitral Valve Insufficiency Transforming growth factor beta Middle Aged medicine.disease Cell biology 030104 developmental biology medicine.anatomical_structure Bone Morphogenetic Proteins biology.protein Mitral Valve Mitral Valve Disorder Female Ex vivo flow model Stress Mechanical Cardiology and Cardiovascular Medicine Myofibroblast |
| Zdroj: | Cardiovascular Research, 116(5), 931-943. OXFORD UNIV PRESS |
| ISSN: | 1755-3245 0008-6363 |
| Popis: | Aims In mitral valve prolapse (MVP), leaflet thickening has recently been suggested to be due, in addition to a myxomatous degeneration, to the presence of a superimposed tissue (SIT), defined as an additional fibrous layer on top of the original leaflet. The mechanisms of SIT formation are currently unknown. We hypothesized that SIT formation would result from excessive leaflet stress and we used a unique ex vivo model to assess the correlation between leaflet remodelling and the type and location of mechanical stress and to elucidate the mechanisms underlying SIT formation. Methods and results Human diseased mitral valves (MVs; n = 21) were histologically analysed for SIT formation and original leaflet thickening. The SIT comprised of various compositions of extracellular matrix and could reach more than 50% of total leaflet thickness. Original leaflet and SIT thickness did not show significant correlation (r = −0.27, P = 0.23), suggesting different regulatory mechanisms. To study the role of the mechanical environment on MV remodelling, mouse MV were cultured in their natural position in the heart and subjected to various haemodynamic conditions representing specific phases of the cardiac cycle and the MVP configuration. SIT formation was induced in the ex vivo model, mostly present on the atrial side, and clearly dependent on the duration, type, and extent of mechanical stress. Specific stainings and lineage tracing experiments showed that SIT comprises of macrophages and myofibroblasts and is associated with the activation of the transforming growth factor-beta and bone morphogenetic protein signalling pathways. Migration of valvular interstitial cells and macrophages through breakages of the endothelial cell lining contributed to SIT formation. Conclusions Mechanical stresses induce specific cellular and molecular changes in the MV that result in SIT formation. These observations provide the first insights in the mechanism of SIT formation and represent an initial step to identify potential novel and early treatment for MVP. |
| Databáze: | OpenAIRE |
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