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Updated: Sep 19, 2025
Echocardiographic Approaches and Protocols for Comprehensive Phenotypic Characterization of Valvular Heart Disease in Mice
Published on: February 14, 2017
Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling
Jesse A Pace1, Lauren M Goddard1, Courtney C Hong1
1Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract:
Myxomatous valve disease (MVD) is the most common form of cardiac valve disease in the developed world. A small fraction of MVD is syndromic and arises in association with matrix protein defects such as those in Marfan syndrome, but most MVD is acquired later in life through an undefined pathogenesis. The KLF2/4 transcription factors mediate endothelial fluid shear responses, including those required to create cardiac valves during embryonic development. Here we test the role of hemodynamic shear forces and downstream endothelial KLF2/4 in mature cardiac valves. We find that loss of hemodynamic forces in heterotopically transplanted hearts or genetic deletion of KLF2/4 in cardiac valve endothelium confers valve cell proliferation and matrix deposition associated with valve thickening, findings also observed in mice expressing the mutant fibrillin-1 protein known to cause human MVD. Transcriptomic and histologic analysis reveals increased monocyte recruitment and TGF-β signaling in both fibrillin-1-mutant valves and valves lacking hemodynamic forces or endothelial KLF2/4 function, but only loss of TGF-β/SMAD signaling rescued myxomatous changes. We observed reduced KLF2/4 expression and augmented SMAD signaling in human MVD. These studies identify hemodynamic activation of endothelial KLF2/4 as an environmental homeostatic regulator of cardiac valves and suggest that non-syndromic MVD may arise in association with disturbed blood flow across the aging valve.
Insights
Disturbed blood flow and reduced KLF2/4 expression contribute to myxomatous valve disease (MVD). Restoring TGF-β/SMAD signaling may offer therapeutic potential for this common cardiac condition.
Area of Science:
- Cardiovascular Biology
- Translational Medicine
- Molecular Cardiology
Background:
- Myxomatous valve disease (MVD) is the leading cause of cardiac valve disease globally.
- While syndromic MVD is linked to genetic defects, the pathogenesis of acquired MVD remains largely unknown.
- Endothelial KLF2/4 transcription factors are crucial for embryonic valve development via fluid shear responses.
Purpose of the Study:
- To investigate the role of hemodynamic shear forces and endothelial KLF2/4 in mature cardiac valves.
- To elucidate the molecular mechanisms underlying acquired MVD.
- To identify potential therapeutic targets for MVD.
Main Methods:
- Utilized heterotopic heart transplantation to alter hemodynamic forces.
- Genetically deleted KLF2/4 in cardiac valve endothelium.
- Performed transcriptomic and histologic analyses.
- Investigated TGF-β/SMAD signaling pathways.
- Examined human MVD patient samples.
Main Results:
- Loss of hemodynamic forces or endothelial KLF2/4 induced valve cell proliferation, matrix deposition, and thickening.
- These changes mimicked MVD observed in fibrillin-1 mutant mice.
- Increased monocyte recruitment and TGF-β signaling were noted in affected valves.
- Only blocking TGF-β/SMAD signaling rescued myxomatous changes.
- Human MVD samples showed reduced KLF2/4 and increased SMAD signaling.
Conclusions:
- Hemodynamic activation of endothelial KLF2/4 is vital for maintaining cardiac valve homeostasis.
- Acquired MVD may result from disturbed blood flow impacting aging valves.
- Dysregulated TGF-β/SMAD signaling is implicated in MVD pathogenesis.
