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

作者：Federico Corti, Yingdi Wang, John Rhodes, Deepak Atri, Stephanie Archer‐Hartmann, Jiasheng Zhang, Zhen W. Zhuang, Dongying Chen, Tianyun Wang, Zhirui Wang, Parastoo Azadi, Michael Simons · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-09605-z · 被引用次数：84 · 研究领域：Proteoglycans and glycosaminoglycans research、Glycosylation and Glycoproteins Research、Angiogenesis and VEGF in Cancer

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 VEGFA 165 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 VEGFA 165 binding sites and formation of a ternary Sdc2-VEGFA 165 -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-VEGFA 165 -VEGFR2 complex formation. This demonstrates the existence of core protein-determined HS sulfation patterns that regulate specific biological activities.