Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction

Abstract

Clinically serious congenital heart valve defects arise from improper growth and remodeling of endocardial cushions into leaflets. Genetic mutations have been extensively studied but explain less than 20% of cases. Mechanical forces generated by beating hearts drive valve development, but how these forces collectively determine valve growth and remodeling remains incompletely understood. Here we decouple the influence of those forces on valve size and shape, and study the role of YAP pathway in determining the size and shape. The low oscillatory shear stress promotes YAP nuclear translocation in valvular endothelial cells (VEC), while the high unidirectional shear stress restricts YAP in cytoplasm. The hydrostatic compressive stress activated YAP in valvular interstitial cells (VIC), whereas the tensile stress deactivated YAP. YAP activation by small molecules promoted VIC proliferation and increased valve size. Whereas YAP inhibition enhanced the expression of cell-cell adhesions in VEC and affected valve shape. Finally, left atrial ligation was performed in chick embryonic hearts to manipulate the shear and hydrostatic stress in-vivo. The restricted flow in the left ventricle induced a globular and hypoplastic left atrioventricular (AV) valves with an inhibited YAP expression. By contrast, the right AV valves with sustained YAP expression grew and elongated normally. This study establishes a simple yet elegant mechanobiological system by which transduction of local stresses regulates valve growth and remodeling. This system guides leaflets to grow into proper sizes and shapes with the ventricular development, without the need of a genetically prescribed timing mechanism.

Data availability

All antibodies, chemicals, and sequences of primers in the study are listed in the Methods. Figure 1 - Source Data 1 and Figure 2 - Source Data 1 Figure 3 - Source Data 1, Figure 4 - Source Data 1 and Figure 5 - Source Data 1 contain the numerical data used to generate the figures.

Article and author information

Author details

  1. Mingkun Wang

    Meinig School of Biomedical Engineering, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Belle Yanyu Lin

    Meinig School of Biomedical Engineering, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shuofei Sun

    Meinig School of Biomedical Engineering, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Charles Dai

    Meinig School of Biomedical Engineering, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Feifei Long

    Meinig School of Biomedical Engineering, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jonathan T Butcher

    Meinig School of Biomedical Engineering, Cornell University, Ithaca, United States
    For correspondence
    jtb47@cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9309-6296

Funding

National Institutes of Health (HL128745)

  • Jonathan T Butcher

National Institutes of Health (HL143247)

  • Jonathan T Butcher

National Institutes of Health (HL160028)

  • Jonathan T Butcher

American Heart Association (821615)

  • Mingkun Wang

National Science Foundation (URoL)

  • Jonathan T Butcher

Additional Ventures Single Ventricle Research Fund

  • Jonathan T Butcher

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mingkun Wang
  2. Belle Yanyu Lin
  3. Shuofei Sun
  4. Charles Dai
  5. Feifei Long
  6. Jonathan T Butcher
(2023)
Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction
eLife 12:e83209.
https://doi.org/10.7554/eLife.83209

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https://doi.org/10.7554/eLife.83209

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