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Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation
Juhyun Lee, … , Alison L. Marsden, Tzung K. Hsiai
Juhyun Lee, … , Alison L. Marsden, Tzung K. Hsiai
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e96672. https://doi.org/10.1172/jci.insight.96672.
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Resource and Technical Advance Cardiology Development

Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation

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Abstract

Hemodynamic shear force has been implicated as modulating Notch signaling–mediated cardiac trabeculation. Whether the spatiotemporal variations in wall shear stress (WSS) coordinate the initiation of trabeculation to influence ventricular contractile function remains unknown. Using light-sheet fluorescent microscopy, we reconstructed the 4D moving domain and applied computational fluid dynamics to quantify 4D WSS along the trabecular ridges and in the groves. In WT zebrafish, pulsatile shear stress developed along the trabecular ridges, with prominent endocardial Notch activity at 3 days after fertilization (dpf), and oscillatory shear stress developed in the trabecular grooves, with epicardial Notch activity at 4 dpf. Genetic manipulations were performed to reduce hematopoiesis and inhibit atrial contraction to lower WSS in synchrony with attenuation of oscillatory shear index (OSI) during ventricular development. γ-Secretase inhibitor of Notch intracellular domain (NICD) abrogated endocardial and epicardial Notch activity. Rescue with NICD mRNA restored Notch activity sequentially from the endocardium to trabecular grooves, which was corroborated by observed Notch-mediated cardiomyocyte proliferations on WT zebrafish trabeculae. We also demonstrated in vitro that a high OSI value correlated with upregulated endothelial Notch-related mRNA expression. In silico computation of energy dissipation further supports the role of trabeculation to preserve ventricular structure and contractile function. Thus, spatiotemporal variations in WSS coordinate trabecular organization for ventricular contractile function.

Authors

Juhyun Lee, Vijay Vedula, Kyung In Baek, Junjie Chen, Jeffrey J. Hsu, Yichen Ding, Chih-Chiang Chang, Hanul Kang, Adam Small, Peng Fei, Cheng-ming Chuong, Rongsong Li, Linda Demer, René R. Sevag Packard, Alison L. Marsden, Tzung K. Hsiai

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Figure 1

ErbB2-dependent trabeculation during cardiac morphogenesis.

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ErbB2-dependent trabeculation during cardiac morphogenesis.
(A) In WT z...
(A) In WT zebrafish embryos, trabecular ridges were absent at 2 dpf. (B) A prominent trabecular ridge developed across the atrioventricular (AV) canal at 3 dpf. Atrial blood flow (red arrows) through the AV canal directly affected the endocardium. White arrows indicate the initial trabecular ridge. Yellow arrows indicate other trabecular ridges. (C) Additional trabecular ridges (yellow arrows) developed on both sides of the initial trabecular ridge at 4 dpf. (D) Trabeculation organized to form an interwoven network at 5 dpf. (E–H) In response to ErbB2 inhibitor (AG1478), trabeculation remained absent in the ventricular wall throughout the cardiac developmental stages. The ventricular wall thickness in response to ErbB2 inhibitor was reduced as compared with that in WT zebrafish embryos. A, atrium; V, ventricle. Scale bar: 50 μm.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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