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Cited by 156Congenital heart defects researchKruppel-like factors researchDevelopmental Biology and Gene Regulation

Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis

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Goddard, Lauren M., Duchemin, Anne-Laure, Ramalingan, Harini, Wu, Bingruo, Chen, Mei, Bamezai, Sharika, Yang, Jisheng, Li, Li +11 more·2017·Developmental Cell
DOI 10.1016/j.devcel.2017.09.023PMC PMC5760194
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Abstract

Hemodynamic forces play an essential epigenetic role in heart valve development, but how they do so is not known. Here, we show that the shear-responsive transcription factor KLF2 is required in endocardial cells to regulate the mesenchymal cell responses that remodel cardiac cushions to mature valves. Endocardial Klf2 deficiency results in defective valve formation associated with loss of Wnt9b expression and reduced canonical WNT signaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b. Studies in zebrafish embryos reveal that wnt9b expression is similarly restricted to the endocardial cells overlying the developing heart valves and is dependent upon both hemodynamic shear forces and klf2a expression. These studies identify KLF2-WNT9B signaling as a conserved molecular mechanism by which fluid forces sensed by endothelial cells direct the complex cellular process of heart valve development and suggest that congenital valve defects may arise due to subtle defects in this mechanotransduction pathway.

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  • By E9.0, fluid shear stress from blood flow and signals from the myocardium including BMPs induce EndMT in a subset of endocardial cells lining the cushions.

    “By E9.0, fluid shear stress from blood flow and signals from the myocardium, including BMPs, induce an endocardial-to-mesenchymal transition (EndMT) in a subset of endocardial cells lining the cushions9–13.”

    From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [12]

    The Introduction (page unavailable) says cushion formation begins at E9.5–10.5 with endocardial-to-mesenchymal transformation, supporting the EndMT component but not the stated E9.0 timing. The Results and Discussion link fluid shear to later cushion remodeling, not to induction of EndMT; the passages found do not identify myocardial BMP signals as an EndMT trigger. (LLM, conf=0.86)

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Authors
Goddard, L. M., Duchemin, A.-L., Ramalingan, H., Wu, B., Chen, M., Bamezai, S., Yang, J., Li, L., Morley, M. P., Wang, T., Scherrer-Crosbie, M., Frank, D. B., Engleka, K. A., Jameson, S. C., Morrisey, E. E., Carroll, T. J., Zhou, B., Vermot, J., & Kahn, M. L.
Affiliations
  • University of Pennsylvania (US)
  • Centre National de la Recherche Scientifique (FR)
  • The University of Texas Southwestern Medical Center (US)
  • Albert Einstein College of Medicine (US)
  • Children's Hospital of Philadelphia (US)
  • University of Minnesota (US)
Corresponding author
Kahn, Mark L.
ORCID
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2017-11
Volume
43
Issue
3
Pages
274-289.e5
ISSN
1534-5807 (ISSN-L)
DOI
10.1016/j.devcel.2017.09.023
PMC
PMC5760194
OpenAlex
W2766557153
Cited by
156
References
3
Citations by year
2026: 16 · 2025: 15 · 2024: 25 · 2023: 15 · 2022: 13 · 2021: 14 · 2020: 25 · 2019: 23 · 2018: 10
FWCI
6.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
  • NIH (R01HL094326, T32HL007954, R0111770, R01116997)
  • Agence Nationale de la Recherche (ANR-15-CE13-0015-01, ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02)
  • European Research Council (682938)
  • Fondation pour la Recherche Médicale (DEQ20140329553)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
heart valve development, KLF2, Wnt9b, paracrine signaling, Wnt/β-catenin signaling, endocardial cells, mesenchymal cells, cardiac cushions, mechanotransduction, zebrafish
MeSH terms
Kruppel-Like Factor 4, Animals, Endocardium, Heart Valves, Hemodynamics, Mice, Transgenic, Transcription Factors, Zebrafish, Signal Transduction, Gene Expression Regulation, Developmental, Zebrafish Proteins, Organogenesis, Cell Proliferation, Wnt Proteins, Kruppel-Like Transcription Factors

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