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.

JAG1-NOTCH4 Mechanosensing Drives Atherosclerosis

“…Polacheck et al demonstrated that physiological shear stress activates NOTCH1 to regulate the composition of adherens junctions and thereby control vascular permeability 14 . Consistent with this, Notch is also activated by physiological HSS during development to permit arterial differentiation 13,36,37 , cardiac morphogenesis 38,39 and valve formation 40 and is also activated by HSS in adult arteries to protect them from atherosclerosis 15 . The expression of JAG1 is also enhanced in HUVEC exposed to shear stress compared to static conditions 41 .…”

Saak Transform-Based Machine Learning for Light-Sheet Imaging of Cardiac Trabeculation

“…The application of Saak transform to segment 3-D LSFM-acquired images creates an opportunity to investigate chemotherapyinduced cardiac structure and mechanics. Previously, we needed to perform manual or semi-automated segmentation to reconstruct LSFM architectures for computational fluid dynamics [15,16] and interactive virtual reality [17,18]. The addition of edge detection to Saak transform enables the calculation of surface area in relation to the volume of myocardium.…”

“…Light-sheet fluorescence microscopy (LSFM) is instrumental in advancing the field of developmental biology and tissue regeneration [1][2][3][4]. LSFM systems have the capacity to investigate cardiac ultra-structure and function [5][6][7][8][9][10][11][12][13][14], providing the moving Baek, Zhaoqiang Wang, Mehrdad Roustaei, Dengfeng Kuang, C.-C. Jay Kuo †, and Tzung K. Hsiai † boundary conditions for computational fluid dynamics [15,16] and the specific labeling of trabecular network for interactive virtual reality [17,18]. However, efficient and robust structural segmentation of cardiac trabeculation remains a post-imaging challenge [19][20][21][22][23].…”

Vascular Injury Changes Topology of Vessel Network to Adapt to Partition of Blood Flow for New Arteriovenous Specification

“…HAEC migration assay was performed as previously described. 9 Areas between inner borders of HAEC at 4, 6, 12, 24 hours post scratch were evaluated using ImageJ. Supplemental Figure 6F shows a schematic representation of how HAEC migration was quantified.…”

“…7 During cardiac morphogenesis, WSS induces the Notch1-ephrinb2-neuregulin 1/erb-b2 receptor tyrosine kinase 2 signaling pathway to initiate cardiac trabeculation. 8,9 Pulsatile and oscillatory WSS differentially regulate Delta/Serrate/Lag ligands in vascular endothelium and smooth muscle cells. 10 The transmembrane ephrinb2 ligand mediates developmental angiogenesis and arteriovenous specifications.…”