Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA.
Complex Carbohydrate Research Center, The University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA.
Nat Commun. 2019 Apr 5;10(1):1562. 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 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 binding sites and formation of a ternary Sdc2-VEGFA-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-VEGFR2 complex formation. This demonstrates the existence of core protein-determined HS sulfation patterns that regulate specific biological activities.
蛋白聚糖 Syndecan-2（Sdc2）已被牵涉到调控细胞骨架组织、整合素信号和斑马鱼发育性血管生成。在这里我们报道说，Sdc2 基因在整体和可诱导的内皮细胞特异性缺失的小鼠中表现出明显的血管生成和动脉生成缺陷，以及 VEGFA 信号受损。在与密切相关的 Syndecan-4（Sdc4）基因缺失的小鼠中则没有观察到这种异常。这些差异归因于 Sdc2 与 Sdc4 硫酸乙酰肝素（HS）链相比，6-O 硫酸化水平显著升高，导致 VEGFA 结合位点增加，并形成三元 Sdc2-VEGFA-VEGFR2 复合物，从而增强 VEGFR2 的激活。增加的 Sdc2 HS 链 6-O 硫酸化是由一个特定的 N 端结构域序列驱动的；将该序列插入 Sdc4 N 端结构域中会增加其 HS 链的 6-O 硫酸化，并促进 Sdc2-VEGFA-VEGFR2 复合物的形成。这表明存在核心蛋白决定的 HS 硫酸化模式，调节特定的生物学活性。
