N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA165-dependent neovascularization
N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA165-dependent neovascularization
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DOI：
10.1038/s41467-019-09605-z
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发表时间：
2019-04-05
影响因子：
16.6
通讯作者：
Simons, Michael
中科院分区：
文献类型：
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作者：
Corti, Federico;Wang, Yingdi;Simons, Michael
蛋白多糖Syndecan-2(Sdc2)参与斑马鱼细胞骨架组织、整合素信号转导和发育中血管生成的调控。在这里，我们报告了具有全局和可诱导的内皮特异性Sdc2缺失的小鼠表现出明显的血管生成和动脉生成缺陷，并损害了VEGFA(165)信号。在密切相关的Syndecan-4(SDC4)基因缺失的小鼠中没有观察到这样的异常。这些差异是由于SDC2链上的6-O硫酸水平显著高于SDC4硫酸乙酰肝素(HS)链，导致VEGFA(165)结合部位的增加，并形成了三元Sdc2-VEGFA(165)-VEGFR2络合物，从而增强了VEGFR2的激活。增加的SDC2 HS链6-O硫酸化是由特定的N-末端结构域序列驱动的；该序列插入SDC4 N-末端结构域增加其HS链的6-O硫酸基化，并促进Sdc2-VEGFA(165)-VEGFR2络合物的形成。这证明了核心蛋白决定的HS硫酸盐化模式的存在，这些模式调节特定的生物活性。
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.