Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/83209 |
| _version_ | 1827953519787769856 |
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| author | Mingkun Wang Belle Yanyu Lin Shuofei Sun Charles Dai Feifei Long Jonathan T Butcher |
| author_facet | Mingkun Wang Belle Yanyu Lin Shuofei Sun Charles Dai Feifei Long Jonathan T Butcher |
| author_sort | Mingkun Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T14:14:24Z |
| format | Article |
| id | doaj.art-a9372ce7eb3a4c55bb2c46c9c7b8f3f3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T14:14:24Z |
| publishDate | 2023-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a9372ce7eb3a4c55bb2c46c9c7b8f3f32023-05-05T14:54:52ZengeLife Sciences Publications LtdeLife2050-084X2023-04-011210.7554/eLife.83209Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransductionMingkun Wang0https://orcid.org/0000-0002-9273-7645Belle Yanyu Lin1Shuofei Sun2Charles Dai3Feifei Long4Jonathan T Butcher5https://orcid.org/0000-0002-9309-6296Meinig School of Biomedical Engineering, Cornell University, Ithaca, United StatesMeinig School of Biomedical Engineering, Cornell University, Ithaca, United StatesMeinig School of Biomedical Engineering, Cornell University, Ithaca, United StatesMeinig School of Biomedical Engineering, Cornell University, Ithaca, United StatesMeinig School of Biomedical Engineering, Cornell University, Ithaca, United StatesMeinig School of Biomedical Engineering, Cornell University, Ithaca, United StatesClinically 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.https://elifesciences.org/articles/83209congenital heart defectmorphogenesismechanobiologymaturationbiomechanics |
| spellingShingle | Mingkun Wang Belle Yanyu Lin Shuofei Sun Charles Dai Feifei Long Jonathan T Butcher Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction eLife congenital heart defect morphogenesis mechanobiology maturation biomechanics |
| title | Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction |
| title_full | Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction |
| title_fullStr | Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction |
| title_full_unstemmed | Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction |
| title_short | Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction |
| title_sort | shear and hydrostatic stress regulate fetal heart valve remodeling through yap mediated mechanotransduction |
| topic | congenital heart defect morphogenesis mechanobiology maturation biomechanics |
| url | https://elifesciences.org/articles/83209 |
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