Sulfated glycans engage the Ang/Tie pathway to regulate vascular development

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 the Tie1 receptor. HS GAGs bound to Ang1/4 ligands and formed ternary Ang-Tie2 receptor complexes, thereby potentiating endothelial survival signaling. In addition, we found that HS GAGs are novel 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.