Fluid shear stress imparts both metabolic and mechanical effects on vascular endothelial function. The spatial ( D/ x) and temporal ( D/ t) components of shear stress largely determine the focal nature of vascular oxidative stress, leading to pro-inflammatory states. The focus of the previous grant period was a paradigm shift in the approach from one of the static models (oxidative biology) to the dynamic models of investigation (vascular oxidative stress) that combined biophysical and biochemical approaches of pathophysiological significance. We demonstrated that variations in D/ x and D/ t differentially regulated the endothelial production of O2.- and .NO, leading to low density lipoprotein (LDL) oxidative modifications relevant for the initiation of atherosclerotic lesions. We developed microelectromechanical systems (MEMS) sensors to measure in real-time intravascular shear stress in the New Zealand White (NZW) rabbits on a hypercholesterolemic diet, and applied our intravascular methodology to the swine model. We gained new insights into the mechanisms whereby atheroprotective hemodynamics increased mitochondrial membrane potential ( (m) accompanied by a decrease in mitochondrial O2.- production via an up-regulation in Mn-SOD activities. In contrast, atherogenic hemodynamics and oxidized LDL induced mitochondrial O2.- production, leading to apoptosis via c-Jun NH2 terminal kinase (JNK)-induced Mn-SOD ubiquitination and protein degradation. Our finding led to a novel observation that active lipid and macrophages in the vessel wall cause electrochemical modifications that can be measured by electrochemical impedance spectroscopy (EIS). In this context, we hypothesize that shear stress regulates mitochondrial redox status, modulating vascular oxidative stress to cause distinct changes in electrochemical impedance in regions of non-obstructive, albeit inflammatory lesions. In the new Aim 1, we will provide an ex vivo model of EIS;specifically, the frequency-dependent electrical and dielectrical properties between concentric bipolar microelectrodes and endoluminal surface of explants of human arteries and NZW rabbit aortas.
In Aim 2, we will establish an in vivo model of EIS measurements using fat-fed NZW rabbits;specifically, microfabrication and deployment of the electrodes for intravascular EIS measurements.
In Aim 3, we will provide molecular and genetic models to demonstrate redox signaling as a requite factor underlying changes in electrochemical modifications. The focus in the next grant period will integrate electrochemical, redox signaling, and genetic approaches to establish specific EIS that occur in response to local pro- inflammatory states during angiograms with the possibility of identifying unstable plaque. In summary, the publication record (30 corresponding authors) of our laboratory in the previous funding cycle is a testimony of our commitment and productivity in mechanobiology and vascular oxidative stress research.

Public Health Relevance

Atherosclerosis is a systemic disease;however, its manifestations tend to be focal and eccentric. We have developed an electrochemical approach to assess LDL oxidation and foam cells in the vessel wall as quantified by electrochemical impedance spectroscopy (EIS). The focus for the next cycle will integrate electrochemical, redox signaling, and genetic approaches to establish specific EIS that occur in response to local pro- inflammatory states with the possibility of identifying unstable plaque when patients undergo angiograms.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-E (02))
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Liu, Lijuan
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University of Southern California
Biomedical Engineering
Schools of Engineering
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
Abiri, Arash; Ding, Yichen; Abiri, Parinaz et al. (2018) Simulating Developmental Cardiac Morphology in Virtual Reality Using a Deformable Image Registration Approach. Ann Biomed Eng 46:2177-2188
Ding, Yichen; Lee, Juhyun; Hsu, Jeffrey J et al. (2018) Light-Sheet Imaging to Elucidate Cardiovascular Injury and Repair. Curr Cardiol Rep 20:35
Ding, Yichen; Bailey, Zachary; Messerschmidt, Victoria et al. (2018) Light-sheet Fluorescence Microscopy for the Study of the Murine Heart. J Vis Exp :
Baek, Kyung In; Ding, Yichen; Chang, Chih-Chiang et al. (2018) Advanced microscopy to elucidate cardiovascular injury and regeneration: 4D light-sheet imaging. Prog Biophys Mol Biol 138:105-115
Ding, Yichen; Ma, Jianguo; Langenbacher, Adam D et al. (2018) Multiscale light-sheet for rapid imaging of cardiopulmonary system. JCI Insight 3:
Baek, Kyung In; Li, Rongsong; Jen, Nelson et al. (2018) Flow-Responsive Vascular Endothelial Growth Factor Receptor-Protein Kinase C Isoform Epsilon Signaling Mediates Glycolytic Metabolites for Vascular Repair. Antioxid Redox Signal 28:31-43
Luo, Yuan; Abiri, Parinaz; Zhang, Shell et al. (2018) Non-Invasive Electrical Impedance Tomography for Multi-Scale Detection of Liver Fat Content. Theranostics 8:1636-1647
Lee, Juhyun; Chou, Tzu-Chieh; Kang, Dongyang et al. (2017) A Rapid Capillary-Pressure Driven Micro-Channel to Demonstrate Newtonian Fluid Behavior of Zebrafish Blood at High Shear Rates. Sci Rep 7:1980
Ding, Yichen; Lee, Juhyun; Ma, Jianguo et al. (2017) Light-sheet fluorescence imaging to localize cardiac lineage and protein distribution. Sci Rep 7:42209

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