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

• Published in: Nature communications 2019-04, Vol.10 (1), p.1562-14, Article 1562
• Main Authors: Corti, Federico, Wang, Yingdi, Rhodes, John M., Atri, Deepak, Archer-Hartmann, Stephanie, Zhang, Jiasheng, Zhuang, Zhen W., Chen, Dongying, Wang, Tianyun, Wang, Zhirui, Azadi, Parastoo, Simons, Michael
• Format: Article
• Language: English
• Subjects: 13/106; 631/443/592/16; 631/80/221; 82/16; 82/58; 82/83; 96/63; 96/95; Abnormalities; Angiogenesis; Binding sites; Chains; Complex formation; Core protein; Cytoskeleton; Gene deletion; Heparan sulfate; Humanities and Social Sciences; Insertion; Mice; multidisciplinary; Proteins; Proteoglycans; Science; Science (multidisciplinary); Signaling; Sulfates; Sulfation; Syndecan; Vascularization; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09605-z

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. Proteoglycans are glycosylated proteins that play a number of structural and signalling functions. Here, Corti, Wang et al. show that the N-terminal sequence of proteoglycan Syndecan-2 selectively increases 6-O sulfation of its heparan sulfate chains, and that this promotes formation of a ternary Sdc2/VEGFA/VEGFR2 complex leading to increased angiogenesis.