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Published Online: 1 January 2018

Flow-Responsive Vascular Endothelial Growth Factor Receptor-Protein Kinase C Isoform Epsilon Signaling Mediates Glycolytic Metabolites for Vascular Repair

Publication: Antioxidants & Redox Signaling
Volume 28, Issue Number 1

Abstract

Aims: Hemodynamic shear stress participates in maintaining vascular redox status. Elucidating flow-mediated endothelial metabolites enables us to discover metabolic biomarkers and therapeutic targets. We posited that flow-responsive vascular endothelial growth factor receptor (VEGFR)-protein kinase C isoform epsilon (PKCɛ)-6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling modulates glycolytic metabolites for vascular repair.
Results: Bidirectional oscillatory flow (oscillatory shear stress [OSS]: 0.1 ± 3 dyne·cm−2 at 1 Hz) upregulated VEGFR-dependent PKCɛ expression to a greater degree than did unidirectional pulsatile flow (pulsatile shear stress [PSS]: 23 ± 8 dyne·cm−2 at 1 Hz) in human aortic endothelial cells (p < 0.05, n = 3). PSS and OSS further upregulated PKCɛ-dependent PFKFB3 expression for glycolysis (p < 0.05, n = 4). Constitutively active PKCɛ increased, whereas dominant-negative PKCɛ reduced both basal and maximal extracellular acidification rates for glycolytic flux (p < 0.01, n = 4). Metabolomic analysis demonstrated an increase in PKCɛ-dependent glycolytic metabolite, dihydroxyacetone (DHA), but a decrease in gluconeogenic metabolite, aspartic acid (p < 0.05 vs. control, n = 6). In a New Zealand White rabbit model, both PKCɛ and PFKFB3 immunostaining was prominent in the PSS- and OSS-exposed aortic arch and descending aorta. In a transgenic Tg(flk-1:EGFP) zebrafish model, GATA-1a morpholino oligonucleotide injection (to reduce viscosity-dependent shear stress) impaired vascular regeneration after tail amputation (p < 0.01, n = 20), which was restored with PKCɛ messenger RNA (mRNA) rescue (p < 0.05, n = 5). As a corollary, siPKCɛ inhibited tube formation and vascular repair, which were restored by DHA treatment in our Matrigel and zebrafish models.
Innovation and Conclusion: Flow-sensitive VEGFR-PKCɛ-PFKFB3 signaling increases the glycolytic metabolite, dihydroxyacetone, to promote vascular repair. Antioxid. Redox Signal. 28, 31–43.

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Published In

cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 28Issue Number 1January 1, 2018
Pages: 31 - 43
PubMed: 28762754

History

Published in print: January 1, 2018
Published online: 1 January 2018
Published ahead of print: 21 September 2017
Published ahead of production: 1 August 2017
Accepted: 31 July 2017
Revision received: 31 July 2017
Received: 8 March 2017

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Kyung In Baek
Department of Bioengineering, School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California.
Rongsong Li
Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
Nelson Jen
Department of Bioengineering, School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California.
Howard Choi
Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
Amir Kaboodrangi
Department of Bioengineering, School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California.
Peipei Ping
Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
Department of Physiology, School of Medicine, University of California, Los Angeles, Los Angeles, California.
David Liem
Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
Tyler Beebe
Department of Bioengineering, School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California.
Tzung K. Hsiai
Department of Bioengineering, School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California.
Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
Department of Physiology, School of Medicine, University of California, Los Angeles, Los Angeles, California.
Greater Los Angeles VA Healthcare System, Los Angeles, California.
Department of Medical Engineering, California Institute of Technology, Pasadena, California.

Notes

Address correspondence to:Prof. Tzung K. HsiaiDivision of CardiologyDepartment of MedicineUniversity of California, Los Angeles10833 Le Conte Avenue, CHS17-054ALos Angeles, CA 90095-1679
Department of BioengineeringUniversity of California, Los Angeles10833 Le Conte Avenue, CHS17-054ALos Angeles, CA 90095-1679E-mail: [email protected]

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No competing financial interests exist.

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