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

Nat Commun. 2019 Apr 5;10(1):1562. doi: 10.1038/s41467-019-09605-z.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Mice
  • Neovascularization, Physiologic / genetics*
  • Protein Domains
  • Retina / growth & development
  • Sequence Analysis, Protein
  • Syndecan-2 / genetics
  • Syndecan-2 / metabolism
  • Syndecan-2 / physiology*
  • Syndecan-4 / genetics
  • Syndecan-4 / metabolism
  • Syndecan-4 / physiology
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor A / physiology*
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / physiology

Substances

  • Sdc2 protein, mouse
  • Sdc4 protein, mouse
  • Syndecan-4
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Syndecan-2
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2