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

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 and Michael Simons ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09605-z

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