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Updated: Jul 20, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome
Connie M Ng1, Alan Cheng, Loretha A Myers
1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract:
Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-beta, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-beta signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. Mitral valves from fibrillin-1-deficient mice exhibited postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-beta activation and signaling. In addition, TGF-beta antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. Expression analyses identified increased expression of numerous TGF-beta-related genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease. These studies validate a novel, genetically engineered murine model of myxomatous changes of the mitral valve and provide critical insight into the pathogenetic mechanism of such changes in MFS and perhaps more common nonsyndromic variants of mitral valve disease.
Insights
Mitral valve prolapse (MVP) pathogenesis involves fibrillin-1 deficiency and enhanced TGF-beta signaling. Targeting TGF-beta in mice with fibrillin-1 mutations reversed MVP-like valve changes, revealing a key mechanism.
Area of Science:
- Cardiovascular Biology
- Connective Tissue Disorders
- Genetic Pathology
Background:
- Mitral valve prolapse (MVP) is a common condition with poorly understood causes.
- MVP can be associated with genetic syndromes like Marfan syndrome (MFS), linked to fibrillin-1 mutations.
- Fibrillin-1 deficiency in MFS leads to increased TGF-beta signaling, implicated in disease pathogenesis.
Purpose of the Study:
- To investigate the role of enhanced TGF-beta signaling in the development of myxomatous mitral valve changes in Marfan syndrome.
- To validate a novel mouse model for studying MVP pathogenesis.
Main Methods:
- Utilized fibrillin-1-deficient mice to model MFS-associated MVP.
- Analyzed mitral valve architecture, cell proliferation, apoptosis, and TGF-beta signaling postnatally.
- Administered TGF-beta antagonist in vivo to assess its effect on the valve phenotype.
- Conducted gene expression analysis of TGF-beta-related pathways.
Main Results:
- Fibrillin-1-deficient mice developed mitral valve architectural alterations.
- These changes correlated with increased cell proliferation, reduced apoptosis, and elevated TGF-beta signaling.
- In vivo TGF-beta antagonism successfully rescued the myxomatous valve phenotype.
- Upregulation of TGF-beta-related genes involved in cell growth and survival was observed.
Conclusions:
- Enhanced TGF-beta signaling is a critical driver of myxomatous mitral valve disease in MFS.
- TGF-beta antagonism presents a potential therapeutic strategy for MFS-related MVP.
- The study establishes a valuable murine model for MVP research, offering insights into both syndromic and non-syndromic forms.
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