Shear Stress and Light-Field to Elucidate the Initiation of Cardiac Outflow Tract Biomechanical forces modulate cardiac morphogenesis, and mutations in mechano-sensitive signaling pathways result in congenital heart defects. During the previous funding cycle, our team custom-built a Light- Sheet Fluorescence Microscopy (LSFM) with sub-voxel resolution to enhance axial resolution needed to provide a large field-of-view. This laser optical system allowed for imaging pulsatile vs. oscillatory shear stress- mediated Notch signaling to initiate endocardial trabeculation. We demonstrated that spatial (??/?x) and temporal (??/?t) variations in shear stress modulates Notch-EphrinB2-Neureguilin-1 signaling in the endocardium to activate erb-B2 receptor tyrosine kinase (ErbB2) that promotes proliferation of trabeculation. By integrating LSFM, computation, and transgenic models, we further established that trabeculation dissipates intracardiac shear stress-generated kinetic energy; thus, mitigating ventricular remodeling. However, it remains unclear what would be the consequences of reduced myocardial contractility or altered intracardiac flow dynamics on valve morphogenesis. Thus, we seek to integrate light-sheet (Bessel-Gaussian beam arrays) with a new 2) light-field (microlens array). The former provides non-diffracting illumination, and the latter provides volumetric detection as a paradigm shift to image both myocardial contractility and intracardiac flow dynamics in the outflow tract (OFT). Our preliminary study reveals that shear-mediated Notch1b expression in the endocardium of OFT regulates endothelial-to-mesenchymal transition (EndoMT); however, the mechanotransduction causation whereby myocardial contractility and intracardiac shear stress reciprocally interact to form bicuspid valves and subsequent remodeling to multi-cuspid valves remains elusive. Thus, our hypothesis is that integration of the new light-field system with imaging computation enhances spatiotemporal resolution needed to decouple myocardial contraction from intracardiac flow dynamics that modulates Notch1b-EndoMT to mediate valve morphogenesis in the OFT.
In Aim 1, we plan to integrate light-sheet with the new light-field system for 4-D volumetric imaging of valve formation in the OFT. Our goal is to capture myocardial contractility and intracardiac shear stress at one snapshot.
In Aim 2, we will demonstrate the interaction between intracardiac shear stress and myocardial contractility underlying valve morphogenesis. Our goal is to decouple hemodynamic shear from contractile forces that mediate Notch1b-mediated EndoMT.
In Aim 3, we will determine the relative role of shear stress and contractility underlying Notch1b-mediated EndoMT. Our goal is to elucidate the relative role of contractility and intracardiac stress to transmit Notch1b- EndoMT signaling underlying bicuspid-valve formation. Overall, our team aims to establish the micro- environment in which intracardiac flow dynamics and myocardial contractility interact to modulate OFT valve formation, with clinical significance to aortic valvular disease.

Public Health Relevance

Cardiac outflow tract (OFT) defects, including aortic valves and the greater arteries, are estimated to cause approximately 30% of these congenital heart diseases, and they are treated with surgical correction and/or replacement. It remains unclear what would be the consequences of reduced cardiac contractility or altered intracardiac flow dynamics on valve morphogenesis, including aortic stenosis, bicuspid or tricuspid aortic valves. To understand the mechanotransduction causation downstream of blood flow and shear stress sensing, we have assembled a multi-disciplinary team to integrate advanced laser optics, imaging computation, and genetic models to decouple intracardiac flow dynamics from myocardial contractility that modulates Notch1b-mediated endothelial-to-mesenchymal transition (EndoMT) with translational implication to aortic valve disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Evans, Frank
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Baek, Kyung In; Packard, René R Sevag; Hsu, Jeffrey J et al. (2018) Ultrafine Particle Exposure Reveals the Importance of FOXO1/Notch Activation Complex for Vascular Regeneration. Antioxid Redox Signal 28:1209-1223
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