Flow-Responsive Vascular Endothelial Growth Factor Receptor-Protein Kinase C Isoform Epsilon Signaling Mediates Glycolytic Metabolites for Vascular Repair.
Antioxid Redox Signal
; 28(1): 31-43, 2018 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-28762754
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 (PKCÉ)-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 PKCÉ 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 PKCÉ-dependent PFKFB3 expression for glycolysis (p < 0.05, n = 4). Constitutively active PKCÉ increased, whereas dominant-negative PKCÉ reduced both basal and maximal extracellular acidification rates for glycolytic flux (p < 0.01, n = 4). Metabolomic analysis demonstrated an increase in PKCÉ-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 PKCÉ and PFKFB3 immunostaining was prominent in the PSS- and OSS-exposed aortic arch and descending aorta. In a transgenic Tg(flk-1EGFP) 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 PKCÉ messenger RNA (mRNA) rescue (p < 0.05, n = 5). As a corollary, siPKCÉ inhibited tube formation and vascular repair, which were restored by DHA treatment in our Matrigel and zebrafish models. Innovation andConclusion:
Flow-sensitive VEGFR-PKCÉ-PFKFB3 signaling increases the glycolytic metabolite, dihydroxyacetone, to promote vascular repair. Antioxid. Redox Signal. 28, 31-43.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fluxo Sanguíneo Regional
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Estresse Mecânico
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Transdução de Sinais
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Receptores de Fatores de Crescimento do Endotélio Vascular
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Células Endoteliais
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Proteína Quinase C-épsilon
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Antioxid Redox Signal
Ano de publicação:
2018
Tipo de documento:
Article