Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation
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
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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Resource and Technical Advance Cardiology Development

Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation

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 8

Elevated OSI values developed in trabecular ridges and are dependent on ventricular surface roughness; OSI revealed distinct differences in the WT versus ErbB2 inhibitor treatment and roughness of ventricular surface.

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Elevated OSI values developed in trabecular ridges and are dependent on ...
(A and B) At 2 and 3 dpf, elevated OSI values were interspersed between trabecular ridges and grooves in the WT embryos. (C and D) At 4 and 5 dpf, high OSI values associated with formation of the trabecular network. (E–G) However, ErbB2 inhibition to attenuate trabeculation abrogated the interspersed OSI at 2, 3, and 4 dpf. (H) Despite a distinct OSI in the WT embryos at 5 dpf, slight interspersion of OSI values appeared in the ErbB2-inhibited group, with consistent absence of the trabecular network. (I) High OSI values were generated in trabecular ridges at 4 dpf. (J) OSI values were substantially reduced after lowering of blood viscosity. (K) ErbB2-inhibited zebrafish showed an attenuated trabecular wall, which stymied oscillatory flow at ventricular walls. (L) Due to a lack of atrial contraction, blood flow acting on the ventricle was low. This generated minimal OSI values. (M) After coinjection of NICD mRNA and gata1a MO, OSI values were reminiscent of those of WT zebrafish due to restored trabeculation.