The angiopoietin (Ang)–Tie pathway is essential for the proper maturation and remodeling of the vasculature. Despite its importance in disease, the mechanisms that control signal transduction through this pathway are poorly understood. Here, we demonstrate that heparan sulfate glycosaminoglycans (HS GAGs) regulate Ang–Tie signaling through direct interactions with both Ang ligands and Tie1 receptors. HS GAGs formed ternary complexes with Ang1 or Ang4 and Tie2 receptors, resulting in potentiation of endothelial survival signaling. In addition, HS GAGs served as ligands for the orphan receptor Tie1. The HS–Tie1 interaction promoted Tie1–Tie2 heterodimerization and enhanced Tie1 stability within the mature vasculature. Loss of HS–Tie1 binding using CRISPR–Cas9-mediated mutagenesis in vivo led to decreased Tie protein levels, pathway suppression and aberrant retinal vascularization. Together, these results reveal that sulfated glycans use dual mechanisms to regulate Ang–Tie signaling and are important for the development and maintenance of the vasculature.

血管生成素 (Ang)-Tie 通路对于脉管系统的适当成熟和重塑至关重要。尽管它在疾病中很重要，但人们对通过该途径控制信号转导的机制知之甚少。在这里，我们证明硫酸乙酰肝素糖胺聚糖 (HS GAG) 通过与 Ang 配体和 Tie1 受体的直接相互作用来调节 Ang-Tie 信号传导。HS GAG 与 Ang1 或 Ang4 和 Tie2 受体形成三元复合物，导致内皮存活信号增强。此外，HS GAG 作为孤儿受体 Tie1 的配体。HS-Tie1 相互作用促进了 Tie1-Tie2 异二聚化并增强了成熟脉管系统内的 Tie1 稳定性。使用 CRISPR-Cas9 介导的体内诱变失去 HS-Tie1 结合导致 Tie 蛋白水平降低，通路抑制和异常的视网膜血管形成。总之，这些结果表明硫酸化聚糖使用双重机制来调节 Ang-Tie 信号传导，并且对于脉管系统的发育和维持很重要。