Journal
NATURE CHEMICAL BIOLOGY
Volume 17, Issue 2, Pages 178-186Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-00657-7
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Funding
- NIH [5R01GM093627, 5R01GM127920]
- National Science Foundation [CBET-1805022, DGE-1144469, DGE-1745301]
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Heparan sulfate glycosaminoglycans (HS GAGs) regulate Ang-Tie signaling by interacting directly with Ang ligands and Tie1 receptors, enhancing endothelial survival signaling and maintaining Tie1 stability within the mature vasculature. Loss of HS-Tie1 binding leads to decreased Tie protein levels, pathway suppression, and aberrant retinal vascularization.
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.
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