Local fluid shear stress operates a molecular switch to drive fetal semilunar valve extension.
cardiovascular development
mechanical regulation
shear stress
valve remodeling
valvulogenesis
Journal
Developmental dynamics : an official publication of the American Association of Anatomists
ISSN: 1097-0177
Titre abrégé: Dev Dyn
Pays: United States
ID NLM: 9201927
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
revised:
01
09
2021
received:
14
04
2021
accepted:
04
09
2021
pubmed:
19
9
2021
medline:
8
4
2022
entrez:
18
9
2021
Statut:
ppublish
Résumé
While much is known about the genetic regulation of early valvular morphogenesis, mechanisms governing fetal valvular growth and remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it is unknown whether or how they interact with valvulogenic signaling programs. Side-specific activity of valvulogenic programs motivates the hypothesis that shear stress pattern-specific endocardial signaling controls the elongation of leaflets. We determined that extension of the semilunar valve occurs via fibrosa sided endocardial proliferation. Low OSS was necessary and sufficient to induce canonical Wnt/β-catenin activation in fetal valve endothelium, which in turn drives BMP receptor/ligand expression, and pSmad1/5 activity essential for endocardial proliferation. In contrast, ventricularis endocardial cells expressed active Notch1 but minimal pSmad1/5. Endocardial monolayers exposed to LSS attenuate Wnt signaling in a Notch1 dependent manner. Low OSS is transduced by endocardial cells into canonical Wnt signaling programs that regulate BMP signaling and endocardial proliferation. In contrast, high LSS induces Notch signaling in endocardial cells, inhibiting Wnt signaling and thereby restricting growth on the ventricular surface. Our results identify a novel mechanically regulated molecular switch, whereby fluid shear stress drives the growth of valve endothelium, orchestrating the extension of the valve in the direction of blood flow.
Sections du résumé
BACKGROUND
While much is known about the genetic regulation of early valvular morphogenesis, mechanisms governing fetal valvular growth and remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it is unknown whether or how they interact with valvulogenic signaling programs. Side-specific activity of valvulogenic programs motivates the hypothesis that shear stress pattern-specific endocardial signaling controls the elongation of leaflets.
RESULTS
We determined that extension of the semilunar valve occurs via fibrosa sided endocardial proliferation. Low OSS was necessary and sufficient to induce canonical Wnt/β-catenin activation in fetal valve endothelium, which in turn drives BMP receptor/ligand expression, and pSmad1/5 activity essential for endocardial proliferation. In contrast, ventricularis endocardial cells expressed active Notch1 but minimal pSmad1/5. Endocardial monolayers exposed to LSS attenuate Wnt signaling in a Notch1 dependent manner.
CONCLUSIONS
Low OSS is transduced by endocardial cells into canonical Wnt signaling programs that regulate BMP signaling and endocardial proliferation. In contrast, high LSS induces Notch signaling in endocardial cells, inhibiting Wnt signaling and thereby restricting growth on the ventricular surface. Our results identify a novel mechanically regulated molecular switch, whereby fluid shear stress drives the growth of valve endothelium, orchestrating the extension of the valve in the direction of blood flow.
Identifiants
pubmed: 34535945
doi: 10.1002/dvdy.419
pmc: PMC8891031
mid: NIHMS1741147
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
481-497Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL128745
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL143247
Pays : United States
Organisme : NIH HHS
ID : S10 OD010605
Pays : United States
Informations de copyright
© 2021 American Association for Anatomy.
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