Cardiac forces regulate zebrafish heart valve delamination by modulating Nfat signaling

Renée Wei-Yan Chow (1) , Hajime Fukui (1, 2) , Wei Xuan Chan (3) , Kok Soon Justin Tan (3) , Stephane Roth (1) , Anne-Laure Duchemin (1) , Nadia Messaddeq (1) , Hiroyuki Nakajima (2) , Fei Liu (4) , Nathalie Faggianelli--Conrozier (1) , Andrey Klymchenko (4) , Yap Choon Hwai (5) , Naoki Mochizuki (2) , Julien Vermot (1, 5)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 National cerebral and cardiovascular center research institute
3 NUS - National University of Singapore
4 LBP - Laboratoire de Bioimagerie et Pathologies
5 Imperial College London

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.

Domaines: Biologie animale

Renée Wei-Yan Chow, Hajime Fukui, Wei Xuan Chan, Kok Soon Justin Tan, Stephane Roth, et al.. Cardiac forces regulate zebrafish heart valve delamination by modulating Nfat signaling. PLoS Biology, 2022, 20 (1), ⟨10.1371/journal.pbio.3001505⟩. ⟨hal-03637858⟩