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Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation

Lee, Juhyun and Vedula, Vijay and Baek, Kyung In and Chen, Junjie and Hsu, Jeffrey J. and Ding, Yichen and Chang, Chih-Chiang and Kang, Hanul and Small, Adam and Fei, Peng and Chuong, Cheng-Ming and Li, Rongsong and Demer, Linda and Packard, René R. Sevag and Marsden, Alison L. and Hsiai, Tzung K. (2018) Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation. JCI insight, 3 (13). Art. No. e96672. ISSN 2379-3708. https://resolver.caltech.edu/CaltechAUTHORS:20180716-102017991

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1172/jci.insight.96672DOIArticle
ORCID:
AuthorORCID
Baek, Kyung In0000-0001-9388-2070
Hsu, Jeffrey J.0000-0002-9971-5916
Ding, Yichen0000-0002-6242-3506
Hsiai, Tzung K.0000-0003-1734-0792
Additional Information:© 2018, American Society for Clinical Investigation. Received: August 9, 2017; Accepted: May 18, 2018. Received: August 9, 2017; Accepted: May 18, 2018. The authors would like to express gratitude to David Traver from UCSD for providing Tg(tp-1:gfp) and to Deborah Yelon from UCSD for providing the wea mutants. This study was supported by the NIH (HL118650 to TKH; HL083015 to TKH, HL111437 to TKH; and HL129727 to TKH and ALM), an American Heart Association Scientist Development Grant (16SDG30910007 to RRSP), and an American Heart Association PreDoctoral Fellowship (15PRE21400019 to JL). Authorship note: JL, VV, and KIB contributed equally to this work. Author contributions: JL, JC, YD, CCC, and PF set up the light-sheet system and imaging. JL, VV, KIB, RRSP, and TKH wrote the manuscript. JL and JJH performed postimaging processing. VV and ALM performed CFD simulation. JL, KIB, YC, and RRSP performed 4D beating zebrafish heart imaging and analysis. AS assisted with linking developmental cardiac mechanics with congenital heart disease. HK and RL prepared DNA clones and in vitro–transcribed RNA. JL, HK, and KIB performed gene expression studies. JL, KIB, and HK performed in vitro experiments. JL, KIB, JC, and HK performed microinjections. CC, RL, ALM, LD, AS, and TKH designed, supervised, revised, and supported the study. The authors have declared that no conflict of interest exists.
Funders:
Funding AgencyGrant Number
NIHHL118650
NIHHL083015
NIHHL111437
NIHHL129727
American Heart Association16SDG30910007
American Heart Association15PRE21400019
Issue or Number:13
Record Number:CaltechAUTHORS:20180716-102017991
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180716-102017991
Official Citation:Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation 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.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:87873
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:16 Jul 2018 17:39
Last Modified:03 Oct 2019 20:00

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