PUBLICATION

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

Authors
Fontana, F., Haack, T., Reichenbach, M., Knaus, P., Puceat, M., Abdelilah-Seyfried, S.
ID
ZDB-PUB-200716-6
Date
2020
Source
Cell Reports   32: 107883 (Journal)
Registered Authors
Abdelilah-Seyfried, Salim
Keywords
Flt4, Klf2, Notch1, biomechanics, endocardium, valvulogenesis, zebrafish
Datasets
GEO:GSE151398
MeSH Terms
  • Animals
  • Heart Valves/embryology*
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Humans
  • Kruppel-Like Transcription Factors
  • Mechanotransduction, Cellular*
  • Mice, Inbred C57BL
  • Organogenesis*
  • Receptor, Notch1/metabolism*
  • Signal Transduction
  • Vascular Endothelial Growth Factor Receptor-3/metabolism*
  • Zebrafish/embryology*
  • Zebrafish Proteins/metabolism*
PubMed
32668254 Full text @ Cell Rep.
Abstract
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes