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Mechanical forces remodel the cardiac extracellular matrix during zebrafish development

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Gentile,  Alessandra
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Albu,  Paula Margareta
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Xu,  Yanli
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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da Silva,  AR
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Stainier,  Didier Y. R.
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Gunawan,  Felix
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Gentile, A., Albu, P. M., Xu, Y., Mortazavi, N., da Silva, A., Stainier, D. Y. R., et al. (2024). Mechanical forces remodel the cardiac extracellular matrix during zebrafish development. DEVELOPMENT, 151(13): dev202310. doi:10.1242/dev.202310.


Cite as: https://hdl.handle.net/21.11116/0000-000F-A6A7-9
Abstract
The cardiac extracellular matrix (cECM) is fundamental for organ morphogenesis and maturation, during which time it undergoes remodeling, yet little is known about whether mechanical forces generated by the heartbeat regulate this remodeling process. Using zebrafish as a model and focusing on stages when cardiac valves and trabeculae form, we found that altering cardiac contraction impairs cECM remodeling. Longitudinal volumetric quantifications in wildtype animals revealed region-specific dynamics: cECM volume decreases in the atrium but not in the ventricle or atrioventricular canal. Reducing cardiac contraction resulted in opposite effects on the ventricular and atrial ECM, whereas increasing the heart rate affected the ventricular ECM but had no effect on the atrial ECM, together indicating that mechanical forces regulate the cECM in a chamber-specific manner. Among the ECM remodelers highly expressed during cardiac morphogenesis, we found one that was upregulated in non-contractile hearts, namely tissue inhibitor of matrix metalloproteinase 2 ( timp2 ). Loss- and gain-of-function analyses of timp2 revealed its crucial role in cECM remodeling. Altogether, our results indicate that mechanical forces control cECM remodeling in part through timp2 downregulation.