Macrophages in the pathophysiology of myxomatous mitral valve dystrophy
Macrophages in the pathophysiology of myxomatous mitral valve dystrophy
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DissertationDate of Exam
24.03.2026Date of Publication
28.05.2026Advisor
Mass, ElviraCo-Referee
Falk, NimmerjahnMetadata
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Abstract
Myxomatous mitral valve dystrophy (MVD) is the first cause of mitral valve prolapse (MVP), a common disease affecting 2 to 3 % of the population. The first causal mutation in the FLNA gene (FLNA-P637Q), was associated with MVD in 2007. Recently, the FLNA-P637Q KI rat model was generated and phenotyped. Using multimodality imaging, MVD was diagnosed as early as 3 weeks and signature of chemotaxis and myeloid cell migration was described at the transcriptomic level. This thesis has attached to determine the dynamic and the role of macrophages in the pathophysiology of MVD.
With a combination of histology, flow cytometry and transcriptomic analysis, the dynamic of MVD development in the FLNA-KI rat model was clarified. Extracellular matrix dysregulation, marked with increased expression of the Hyaluronan synthase Has1, is present as early as birth, quickly followed by endothelial dysfunction by two days post-natal, and marked by overexpression of the endothelial stress marker Esm1. Morphological remodeling of the MV is detectable from seven days post-natal, and is accompanied by an upregulation of chemotactic signaling as assessed by bulk RNA sequencing. However, no differences in the proportion of immune cells is seen at this timepoint. At the age of three weeks, the proportion of macrophages is significantly increase in the MV of KI rats. We also corroborated the contributions of macrophages to MVD in a large cohort of Human MVD samples. We then assessed macrophages core function, phagocytosis, upon FLNA P637Q mutation and found no differences. Finally, using single nuclei RNAseq, we tried to decipher the cellular landscape of the MV at steady state and during MVD and identify the interactions between macrophages and the other cell types contributing to the disease.
Overall, this thesis highlight the contribution of macrophages to the myxomatous remodeling of the mitral valve, and pave the way to the study of macrophages interactions with the MV environment to better understand what role do they play in the development and the maintenance of MVD. This could potentially lead to the identification of new therapeutic target that could greatly improve the quality of treatment offered to patients.
With a combination of histology, flow cytometry and transcriptomic analysis, the dynamic of MVD development in the FLNA-KI rat model was clarified. Extracellular matrix dysregulation, marked with increased expression of the Hyaluronan synthase Has1, is present as early as birth, quickly followed by endothelial dysfunction by two days post-natal, and marked by overexpression of the endothelial stress marker Esm1. Morphological remodeling of the MV is detectable from seven days post-natal, and is accompanied by an upregulation of chemotactic signaling as assessed by bulk RNA sequencing. However, no differences in the proportion of immune cells is seen at this timepoint. At the age of three weeks, the proportion of macrophages is significantly increase in the MV of KI rats. We also corroborated the contributions of macrophages to MVD in a large cohort of Human MVD samples. We then assessed macrophages core function, phagocytosis, upon FLNA P637Q mutation and found no differences. Finally, using single nuclei RNAseq, we tried to decipher the cellular landscape of the MV at steady state and during MVD and identify the interactions between macrophages and the other cell types contributing to the disease.
Overall, this thesis highlight the contribution of macrophages to the myxomatous remodeling of the mitral valve, and pave the way to the study of macrophages interactions with the MV environment to better understand what role do they play in the development and the maintenance of MVD. This could potentially lead to the identification of new therapeutic target that could greatly improve the quality of treatment offered to patients.
Subjects
mitral valve, valvulopathy, macrophages, mitral valve disease
Classification (DDC)
570 Biowissenschaften, BiologieLe Vely, Benjamin: Macrophages in the pathophysiology of myxomatous mitral valve dystrophy. - Bonn, 2026. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-89636
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-89636
@phdthesis{handle:20.500.11811/14172,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-89636,
author = {{Benjamin Le Vely}},
title = {Macrophages in the pathophysiology of myxomatous mitral valve dystrophy},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2026,
month = may,
note = {Myxomatous mitral valve dystrophy (MVD) is the first cause of mitral valve prolapse (MVP), a common disease affecting 2 to 3 % of the population. The first causal mutation in the FLNA gene (FLNA-P637Q), was associated with MVD in 2007. Recently, the FLNA-P637Q KI rat model was generated and phenotyped. Using multimodality imaging, MVD was diagnosed as early as 3 weeks and signature of chemotaxis and myeloid cell migration was described at the transcriptomic level. This thesis has attached to determine the dynamic and the role of macrophages in the pathophysiology of MVD.
With a combination of histology, flow cytometry and transcriptomic analysis, the dynamic of MVD development in the FLNA-KI rat model was clarified. Extracellular matrix dysregulation, marked with increased expression of the Hyaluronan synthase Has1, is present as early as birth, quickly followed by endothelial dysfunction by two days post-natal, and marked by overexpression of the endothelial stress marker Esm1. Morphological remodeling of the MV is detectable from seven days post-natal, and is accompanied by an upregulation of chemotactic signaling as assessed by bulk RNA sequencing. However, no differences in the proportion of immune cells is seen at this timepoint. At the age of three weeks, the proportion of macrophages is significantly increase in the MV of KI rats. We also corroborated the contributions of macrophages to MVD in a large cohort of Human MVD samples. We then assessed macrophages core function, phagocytosis, upon FLNA P637Q mutation and found no differences. Finally, using single nuclei RNAseq, we tried to decipher the cellular landscape of the MV at steady state and during MVD and identify the interactions between macrophages and the other cell types contributing to the disease.
Overall, this thesis highlight the contribution of macrophages to the myxomatous remodeling of the mitral valve, and pave the way to the study of macrophages interactions with the MV environment to better understand what role do they play in the development and the maintenance of MVD. This could potentially lead to the identification of new therapeutic target that could greatly improve the quality of treatment offered to patients.},
url = {https://hdl.handle.net/20.500.11811/14172}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-89636,
author = {{Benjamin Le Vely}},
title = {Macrophages in the pathophysiology of myxomatous mitral valve dystrophy},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2026,
month = may,
note = {Myxomatous mitral valve dystrophy (MVD) is the first cause of mitral valve prolapse (MVP), a common disease affecting 2 to 3 % of the population. The first causal mutation in the FLNA gene (FLNA-P637Q), was associated with MVD in 2007. Recently, the FLNA-P637Q KI rat model was generated and phenotyped. Using multimodality imaging, MVD was diagnosed as early as 3 weeks and signature of chemotaxis and myeloid cell migration was described at the transcriptomic level. This thesis has attached to determine the dynamic and the role of macrophages in the pathophysiology of MVD.
With a combination of histology, flow cytometry and transcriptomic analysis, the dynamic of MVD development in the FLNA-KI rat model was clarified. Extracellular matrix dysregulation, marked with increased expression of the Hyaluronan synthase Has1, is present as early as birth, quickly followed by endothelial dysfunction by two days post-natal, and marked by overexpression of the endothelial stress marker Esm1. Morphological remodeling of the MV is detectable from seven days post-natal, and is accompanied by an upregulation of chemotactic signaling as assessed by bulk RNA sequencing. However, no differences in the proportion of immune cells is seen at this timepoint. At the age of three weeks, the proportion of macrophages is significantly increase in the MV of KI rats. We also corroborated the contributions of macrophages to MVD in a large cohort of Human MVD samples. We then assessed macrophages core function, phagocytosis, upon FLNA P637Q mutation and found no differences. Finally, using single nuclei RNAseq, we tried to decipher the cellular landscape of the MV at steady state and during MVD and identify the interactions between macrophages and the other cell types contributing to the disease.
Overall, this thesis highlight the contribution of macrophages to the myxomatous remodeling of the mitral valve, and pave the way to the study of macrophages interactions with the MV environment to better understand what role do they play in the development and the maintenance of MVD. This could potentially lead to the identification of new therapeutic target that could greatly improve the quality of treatment offered to patients.},
url = {https://hdl.handle.net/20.500.11811/14172}
}
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