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Research ArticleCellular and Molecular

The Cytochrome P450 4A/F-20-Hydroxyeicosatetraenoic Acid System: A Regulator of Endothelial Precursor Cells Derived from Human Umbilical Cord Blood

Austin M. Guo, Branislava Janic, Ju Sheng, John R. Falck, Richard J. Roman, Paul A. Edwards, Ali S. Arbab and A. Guillermo Scicli
Journal of Pharmacology and Experimental Therapeutics August 2011, 338 (2) 421-429; DOI: https://doi.org/10.1124/jpet.111.179036
Austin M. Guo
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Branislava Janic
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Ju Sheng
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John R. Falck
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Richard J. Roman
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Paul A. Edwards
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Ali S. Arbab
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A. Guillermo Scicli
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This article has a correction. Please see:

  • Correction to “The Cytochrome P450 4A/F-20-Hydroxyeicosatetraenoic Acid System: A Regulator of Endothelial Precursor Cells Derived from Human Umbilical Cord Blood” - February 01, 2012

Abstract

Endothelial progenitor cells (EPCs) contribute to physiological and pathological neovascularization. Previous data have suggested that the cytochrome P450 4A/F (CYP4A/F)-20-hydroxyeicosatetraenoic acid (20-HETE) system regulates neovascularization. Therefore, we studied whether the angiogenic effects of the CYP4A/F-20-HETE system involve regulation of EPC function. We extracted human umbilical cord blood and isolated EPCs, which express AC133+CD34+ and kinase insert domain receptor (KDR) surface markers and contain mRNA and protein for CYP4A11 and CYP4A22 enzymes, as opposed to mesenchymal stem cells, which only express negligible amounts of CYP4A11/22. When EPCs were incubated with arachidonic acid, they produced 20-HETE, which stimulated the cells to proliferate and migrate, as did vascular endothelial growth factor. Incubation with 1 μM N-hydroxy-N′-(4-butyl-2-methylphenyl)formamidine (HET0016), a selective inhibitor of 20-HETE synthesis, reduced the proliferative and migratory effects of vascular endothelial growth factor and also significantly abolished EPC migration mediated by stroma-derived factor-1α, as did (6,15) 20-hydroxyeicosadienoic acid. Coculturing EPCs and endothelial cells on a Matrigel matrix led to tube formation, which in turn was inhibited by both HET0016 and 20-hydroxyeicosadienoic acid. We concluded that the CYP4A/F-20-HETE system is expressed in EPCs and can act as both an autocrine and a paracrine regulatory factor.

Footnotes

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL036279, HL029587] (to R.J.R.); the National Institutes of Health National Cancer Institute [Grants R01-CA122031, R21-CA129801-01A1] (to A.S.A.); the National Institutes of Health National Institute of General Medical Sciences [Grant GM31278] (to J.R.F.); the American Heart Association [Grant 09SDG2230011] (to B.J.); and the Robert A. Welch Foundation [Grant GL625910] (to J.R.F.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.179036.

  • ABBREVIATIONS:

    EPC
    endothelial progenitor cell
    20-HEDE
    (6,15) 20-hydroxyeicosadienoic acid
    20-HETE
    20-hydroxyeicosatetraenoic acid
    AA
    arachidonic acid
    Ct
    threshold cycle
    CXCR4
    chemokine receptor type 4
    CYP4A/F
    cytochrome P450 4A/F
    EC
    endothelial cell
    HET0016
    N-hydroxy-N′-(4-butyl-2-methylphenyl)formamidine
    HIF-1α
    hypoxia-inducible factor-1α
    VE
    vascular endothelial
    MSC
    mesenchymal stem cell
    PCR
    polymerase chain reaction
    KDR
    kinase insert domain receptor
    RT
    reverse transcription
    SDF-1α
    stroma-derived factor-1α
    VEGF
    vascular endothelial growth factor
    bp
    basepairs
    DDMS
    N-methylsulfonyl-12,12-dibromododec-11-enamide
    PG
    prostaglandin
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry.

  • Received January 11, 2011.
  • Accepted April 27, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 2
1 Aug 2011
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Research ArticleCellular and Molecular

The Cytochrome P450 4A/F-20-Hydroxyeicosatetraenoic Acid System: A Regulator of Endothelial Precursor Cells Derived from Human Umbilical Cord Blood

Austin M. Guo, Branislava Janic, Ju Sheng, John R. Falck, Richard J. Roman, Paul A. Edwards, Ali S. Arbab and A. Guillermo Scicli
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 421-429; DOI: https://doi.org/10.1124/jpet.111.179036

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Research ArticleCellular and Molecular

The Cytochrome P450 4A/F-20-Hydroxyeicosatetraenoic Acid System: A Regulator of Endothelial Precursor Cells Derived from Human Umbilical Cord Blood

Austin M. Guo, Branislava Janic, Ju Sheng, John R. Falck, Richard J. Roman, Paul A. Edwards, Ali S. Arbab and A. Guillermo Scicli
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 421-429; DOI: https://doi.org/10.1124/jpet.111.179036
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