Cardiac forces regulate zebrafish heart valve delamination by modulating Nfat signaling

• Published in: PLoS biology 2022-01, Vol.20 (1), p.e3001505-e3001505
• Main Authors: Chow, Renee Wei-Yan, Fukui, Hajime, Chan, Wei Xuan, Tan, Kok Soon Justin, Roth, Stéphane, Duchemin, Anne-Laure, Messaddeq, Nadia, Nakajima, Hiroyuki, Liu, Fei, Faggianelli-Conrozier, Nathalie, Klymchenko, Andrey S, Choon Hwai, Yap, Mochizuki, Naoki, Vermot, Julien
• Format: Article
• Language: English
• Subjects: Animal biology; Animals; Animals, Genetically Modified; Biology and Life Sciences; Blood; Blood flow; Cushions; Danio rerio; Defects; Delamination; Developmental stages; Embryo, Nonmammalian; Embryos; Endothelium; Heart; Heart - embryology; Heart function; Heart valves; Heart Valves - abnormalities; Hemodynamics; Hemorheology; Life Sciences; Mechanical Phenomena; Mechanical properties; Mechanical stimuli; Medicine and Health Sciences; Mesenchyme; Mesoderm; Modulators; Morphogenesis; Morphology; NF-AT protein; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Perturbation; Physical Sciences; Physiological aspects; Research and Analysis Methods; Valve leaflets; Zebra fish; Zebrafish; Zebrafish - embryology; Zebrafish - genetics
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3001505

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.