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Vascular endothelial growth factor-A inhibits EphB4 and stimulates delta-like ligand 4 expression in adult endothelial cells

  • Chenzi Yang
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

    Department of Vascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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  • Yuanyuan Guo
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Caroline C. Jadlowiec
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, University of Connecticut, Farmington, Connecticut
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  • Xin Li
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

    Department of Vascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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  • Wei Lv
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Shandong University School of Medicine, Shandong, Jinan, China
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  • Lynn S. Model
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Michael J. Collins
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Yuka Kondo
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Akihito Muto
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Chang Shu
    Affiliations
    Department of Vascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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  • Alan Dardik
    Correspondence
    Corresponding author. Department of Surgery, Yale University School of Medicine, 10 Amistad Street, Room 437, PO Box 208089, New Haven, CT 06520-8089. Tel.: +1 203 737 2082; fax: +1 203 737 2290.
    Affiliations
    Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

    Department of Surgery, VA Connecticut Healthcare System, West Haven, Connecticut
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Published:February 04, 2013DOI:https://doi.org/10.1016/j.jss.2013.01.009

      Abstract

      Background

      During vein graft adaptation to the arterial circulation, vascular endothelial growth factor (VEGF) A expression transiently increases before becoming downregulated; however, the role of VEGF-A in venous remodeling is not clear. In addition, although VEGF-A stimulates angiogenesis and determines arterial identity in nascent arterial endothelial cells (EC), the role of VEGF-A in regulating identity in adult venous EC is also not clear.

      Materials and methods

      EC, wild type (EphB4+/+) or heterozygous knockout (EphB4+/−), were stimulated with VEGF-A (0–100 ng/mL) and examined with quantitative polymerase chain reaction and western blotting.

      Results

      VEGF-A (100 ng/mL) inhibited expression of EphB4 and stimulated expression of delta-like ligand 4 (dll4) but did not stimulate either notch or EphrinB2 expression in adult venous EC. Pretreatment with VEGF receptor 2–neutralizing antibody abolished VEGF-stimulated downregulation of EphB4 but not the upregulation of dll4. Pretreatment with PD98059 or wortmannin showed that VEGF-A downregulation of EphB4 and upregulation of dll4 are mitogen-activated protein kinase kinase and extracellular signal–regulated kinase dependent but phosphatidylinositol 3 kinase–Akt independent. Compared with VEGF-induced EphB4 downregulation and dll4 upregulation in control EC, reduced EphB4 signaling in EphB4+/− EC showed even further downregulation of EphB4 and upregulation of dll4.

      Conclusions

      Despite the genetic programming of arterial and venous EC fate, VEGF-A can repress venous identity in adult venous EC without induction of arterial identity. These changes in adult EC in vitro recapitulate the changes in identity described during vein graft adaptation to the arterial environment in vivo.

      Keywords

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