Abstract
In the clinic, most cases of congenital heart valve defects are thought to arise through errors that occur after the endothelial–mesenchymal transition (EndoMT) stage of valve development. Although mechanical forces caused by heartbeat are essential modulators of cardiovascular development, their role in these later developmental events is poorly understood. To address this question, we used the zebrafish superior atrioventricular valve (AV) as a model. We found that cellularized cushions of the superior atrioventricular canal (AVC) morph into valve leaflets via mesenchymal–endothelial transition (MEndoT) and tissue sheet delamination. Defects in delamination result in thickened, hyperplastic valves, and reduced heart function. Mechanical, chemical, and genetic perturbation of cardiac forces showed that mechanical stimuli are important regulators of valve delamination. Mechanistically, we show that forces modulate Nfatc activity to control delamination. Together, our results establish the cellular and molecular signature of cardiac valve delamination in vivo and demonstrate the continuous regulatory role of mechanical forces and blood flow during valve formation.
Highlights
Heart valves are structures critical for ensuring unidirectional blood flow, and heart valve disease is a significant cause of illness and death worldwide
Heart valve development is initiated by the endothelial–mesenchymal transition (EndoMT) of a subset of endocardial cells, which migrate into the cardiac jelly (CJ) and subsequently
Until 80 hpf, we find that valve leaflets tend to fold in stopped hearts such that the inner layer of valve endocardial cells is in contact with endocardial cells of the atrioventricular canal (AVC) wall (Fig 1F–1F””’, S2A–A””’ and S2B–S2B””’ Fig)
Summary
Heart valves are structures critical for ensuring unidirectional blood flow, and heart valve disease is a significant cause of illness and death worldwide. Given the intimate relationship between cardiac forces and cardiovascular development [1,2,3,4,5], a better understanding of how mechanical forces regulate heart valve morphogenesis can yield valuable insights into the origins of heart valve disease. Heart valve development is initiated by the endothelial–mesenchymal transition (EndoMT) of a subset of endocardial cells, which migrate into the cardiac jelly (CJ) and subsequently. The average intensity per single dot is given by Intensitydot P20 i
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