# Exercise-Induced Shear Stress Modulates Metabolic Pathways for Vascular Repair and Protection

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2022 · —

## Abstract

Exercise-Induced Shear Stress Modulates Metabolic Pathways for Vascular Repair and Protection
Cardiovascular and metabolic diseases are on the rise in our veterans returning from battlefields in
Afghanistan and the Middle East, and exercise intervention remains an effective lifestyle modification.
Hemodynamic stress forces modulate both metabolic and mechanical effects on vascular endothelial cells,
mediating the focal and eccentric nature of atherosclerotic lesions. The advent in metabolomics and metabolic
profiling has led to the discovery of new metabolic biomarkers and therapeutic targets. We established that
bidirectional oscillatory flow impairs autophagic flux, perturbing mitochondrial homeostasis. In contrast,
unidirectional pulsatile flow attenuated mitochondrial DNA damage to maintain endothelial homeostasis. In
parallel, we developed flexible micro-electrochemical impedance sensors for detection of metabolically active
atherosclerotic lesions in the New Zealand White (NZW) rabbit model. We demonstrated that oxidized Low-
Density Lipoprotein (oxLDL) in atherosclerotic lesions display distinct frequency-dependent electrical and
dielectrical properties. Our preliminary studies revealed that pulsatile and oscillatory flow differentially
modulated metabolic pathways to promote vascular regeneration and athero-protection. We demonstrated that
flow-sensitive arterial metabolic changes were detected by electrochemical impedance spectroscopy (EIS).
Furthermore, our metabolomics analyses revealed that PSS vs. OSS differentially activates PKCɛ-6-
phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling to increase glycolytic metabolites,
but to decrease gluconeogenic metabolites, for vascular repair and regeneration. Metabolomics analyses
further uncovered flow-sensitive nuclear hormone receptor peroxisome proliferator-activated receptor 
(PPAR)-dependent fatty acid metabolites to mitigate monocyte recruitment. In this context, we hypothesize
that exercise-augmented pulsatile shear stress (PSS) modulates glycolytic and lipid metabolic
pathways to influence vascular regeneration and protection, leading to the arterial metabolic changes
that can be detected by 3-D EIS mapping. To test our hypothesis, we have three aims. In Aim 1, we will
determine if flow-mediated PKCε signaling modulates glycolytic metabolites for vascular regeneration. We
hypothesize that PSS and OSS differentially modulate PKCε-PFKFB3 signaling pathway to regulate production
of glycolytic metabolites. In Aim 2, we will determine if flow-sensitive PPAR signaling modulates lipid
metabolites for vascular protection. We hypothesize that PSS and OSS differentially modulate PPAR-SCD-1
signaling to regulate production of fatty acid metabolites. In Aim 3, we will demonstrate shear stress-PPAR-
mediated arterial metabolic changes by 3-D EIS mapping. We hypothesize that PPAR-SCD1-mediated
metabolic changes can be interrogated by 3-D EIS mapping. Overall, the integratio...

## Key facts

- **NIH application ID:** 10436918
- **Project number:** 5I01BX004356-04
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Tzung K Hsiai
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436918

## Citation

> US National Institutes of Health, RePORTER application 10436918, Exercise-Induced Shear Stress Modulates Metabolic Pathways for Vascular Repair and Protection (5I01BX004356-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10436918. Licensed CC0.

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