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Antagonistic Activities of Vegfr3/Flt4 and Notch1b Fine-tune Mechanosensitive Signaling during Zebrafish Cardiac Valvulogenesis

The formation of cardiac valves depends on mechanical forces exerted by blood flow. Endocardial cells lining the interior of the heart are sensitive to these stimuli and respond by rearranging into luminal cells subjected to shear stress and abluminal cells not exposed to it. The mechanisms by which...

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Published in:Cell reports (Cambridge) 2020-07, Vol.32 (2), p.107883-107883, Article 107883
Main Authors: Fontana, Federica, Haack, Timm, Reichenbach, Maria, Knaus, Petra, Puceat, Michel, Abdelilah-Seyfried, Salim
Format: Article
Language:English
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Summary:The formation of cardiac valves depends on mechanical forces exerted by blood flow. Endocardial cells lining the interior of the heart are sensitive to these stimuli and respond by rearranging into luminal cells subjected to shear stress and abluminal cells not exposed to it. The mechanisms by which endocardial cells sense these dynamic biomechanical stimuli and how they evoke different cellular responses are largely unknown. Here, we show that blood flow activates two parallel mechanosensitive pathways, one mediated by Notch and the other by Klf2a. Both pathways negatively regulate the angiogenesis receptor Vegfr3/Flt4, which becomes restricted to abluminal endocardial cells. Its loss disrupts valve morphogenesis and results in the occurrence of Notch signaling within abluminal endocardial cells. Our work explains how antagonistic activities by Vegfr3/Flt4 on the abluminal side and by Notch on the luminal side shape cardiac valve leaflets by triggering unique differences in the fates of endocardial cells. [Display omitted] •Flt4 is suppressed by fluid shear stress within the atrioventricular valve leaflet•Fluid shear stress activates Notch and Klf2a signaling in an independent manner•The Klf2a and Notch pathways repress Flt4•Notch and Flt4 work antagonistically to shape the atrioventricular valve Fontana et al. show that cardiac atrioventricular valve formation in zebrafish requires blood flow-induced shear stress to trigger differences in endocardial cell fates. The induction of Notch and Klf2a represses the expression of Flt4. In turn, Flt4 prevents Notch activity within no-flow regions. This fine-tuned mechanism shapes cardiac valve morphogenesis.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.107883