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

被引：51

作者：

Corti, Federico ^{[1
]}

Wang, Yingdi ^{[1
]}

Rhodes, John M. ^{[1
]}

Atri, Deepak ^{[1
]}

Archer-Hartmann, Stephanie ^{[2
]}

Zhang, Jiasheng ^{[1
]}

Zhuang, Zhen W. ^{[1
]}

Chen, Dongying ^{[1
]}

Wang, Tianyun ^{[1
]}

Wang, Zhirui ^{[2
]}

Azadi, Parastoo ^{[2
]}

Simons, Michael ^{[1
,3
]}

机构：

[1] Yale Univ, Sch Med, Dept Internal Med, Yale Cardiovasc Res Ctr,Sect Cardiovasc Med, 300 George St, New Haven, CT 06511 USA

[2] Univ Georgia, Complex Carbohydrate Res Ctr, 315 Riverbend Rd, Athens, GA 30602 USA

[3] Yale Univ, Sch Med, Dept Cell Biol, 333 Cedar St, New Haven, CT 06520 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家卫生研究院;

关键词：

ENDOTHELIAL GROWTH-FACTOR; GLAND EPITHELIAL-CELLS; VEGF; ACTIVATION; ANGIOGENESIS; BINDING; INTEGRIN; GENE; RECEPTORS; PROTEOGLYCAN;

D O I：

10.1038/s41467-019-09605-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

共 72 条

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