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

Baek, Kyung In and Li, Rongsong and Jen, Nelson and Choi, Howard and Kaboodrangi, Amir and Ping, Peipei and Liem, David and Beebe, Tyler and Hsiai, Tzung K. (2018) Flow-Responsive Vascular Endothelial Growth Factor Receptor-Protein Kinase C Isoform Epsilon Signaling Mediates Glycolytic Metabolites for Vascular Repair. Antioxidants and Redox Signaling, 28 (1). pp. 31-43. ISSN 1523-0864. http://resolver.caltech.edu/CaltechAUTHORS:20170925-081332206

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1089/ars.2017.7044DOIArticle
http://online.liebertpub.com/doi/10.1089/ars.2017.7044PublisherArticle
Alternate Title:Flow-Responsive VEGFR-PKCɛ Signaling Mediates Glycolytic Metabolites for Vascular Repair
Additional Information:© 2017 Mary Ann Liebert, Inc. publishers. Online Ahead of Print: September 21, 2017; Online Ahead of Editing: August 1, 2017.
Record Number:CaltechAUTHORS:20170925-081332206
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20170925-081332206
Official Citation:Baek Kyung In, Li Rongsong, Jen Nelson, Choi Howard, Kaboodrangi Amir, Ping Peipei, Liem David, Beebe Tyler, and Hsiai Tzung K.. Antioxidants & Redox Signaling. January 2018, 28(1): 31-43. https://doi.org/10.1089/ars.2017.7044
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:81792
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:25 Sep 2017 17:41
Last Modified:14 Dec 2017 23:09

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