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N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA165-dependent neovascularization

Author

Listed:
  • Federico Corti

    (Yale University School of Medicine)

  • Yingdi Wang

    (Yale University School of Medicine)

  • John M. Rhodes

    (Yale University School of Medicine)

  • Deepak Atri

    (Yale University School of Medicine)

  • Stephanie Archer-Hartmann

    (The University of Georgia)

  • Jiasheng Zhang

    (Yale University School of Medicine)

  • Zhen W. Zhuang

    (Yale University School of Medicine)

  • Dongying Chen

    (Yale University School of Medicine)

  • Tianyun Wang

    (Yale University School of Medicine)

  • Zhirui Wang

    (The University of Georgia)

  • Parastoo Azadi

    (The University of Georgia)

  • Michael Simons

    (Yale University School of Medicine
    Yale University School of Medicine)

Abstract

The proteoglycan Syndecan-2 (Sdc2) has been implicated in regulation of cytoskeleton organization, integrin signaling and developmental angiogenesis in zebrafish. Here we report that mice with global and inducible endothelial-specific deletion of Sdc2 display marked angiogenic and arteriogenic defects and impaired VEGFA165 signaling. No such abnormalities are observed in mice with deletion of the closely related Syndecan-4 (Sdc4) gene. These differences are due to a significantly higher 6-O sulfation level in Sdc2 versus Sdc4 heparan sulfate (HS) chains, leading to an increase in VEGFA165 binding sites and formation of a ternary Sdc2-VEGFA165-VEGFR2 complex which enhances VEGFR2 activation. The increased Sdc2 HS chains 6-O sulfation is driven by a specific N-terminal domain sequence; the insertion of this sequence in Sdc4 N-terminal domain increases 6-O sulfation of its HS chains and promotes Sdc2-VEGFA165-VEGFR2 complex formation. This demonstrates the existence of core protein-determined HS sulfation patterns that regulate specific biological activities.

Suggested Citation

  • Federico Corti & Yingdi Wang & John M. Rhodes & Deepak Atri & Stephanie Archer-Hartmann & Jiasheng Zhang & Zhen W. Zhuang & Dongying Chen & Tianyun Wang & Zhirui Wang & Parastoo Azadi & Michael Simons, 2019. "N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA165-dependent neovascularization," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09605-z
    DOI: 10.1038/s41467-019-09605-z
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