Dual Action of Sulfated Hyaluronan on Angiogenic Processes in Relation to Vascular Endothelial Growth Factor-A

Sci Rep. 2019 Dec 2;9(1):18143. doi: 10.1038/s41598-019-54211-0.

Abstract

Pathological healing characterized by abnormal angiogenesis presents a serious burden to patients' quality of life requiring innovative treatment strategies. Glycosaminoglycans (GAG) are important regulators of angiogenic processes. This experimental and computational study revealed how sulfated GAG derivatives (sGAG) influence the interplay of vascular endothelial growth factor (VEGF)165 and its heparin-binding domain (HBD) with the signaling receptor VEGFR-2 up to atomic detail. There was profound evidence for a HBD-GAG-HBD stacking configuration. Here, the sGAG act as a "molecular glue" leading to recognition modes in which sGAG interact with two VEGF165-HBDs. A 3D angiogenesis model demonstrated the dual regulatory role of high-sulfated derivatives on the biological activity of endothelial cells. While GAG alone promote sprouting, they downregulate VEGF165-mediated signaling and, thereby, elicit VEGF165-independent and -dependent effects. These findings provide novel insights into the modulatory potential of sGAG derivatives on angiogenic processes and point towards their prospective application in treating abnormal angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chondroitin Sulfates / pharmacology
  • Computer Simulation
  • Glycosaminoglycans / chemistry
  • Glycosaminoglycans / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hyaluronic Acid / pharmacology*
  • Immobilized Proteins / metabolism
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Neovascularization, Physiologic
  • Phosphorylation
  • Protein Domains
  • Spheroids, Cellular
  • Structure-Activity Relationship
  • Surface Plasmon Resonance
  • Vascular Endothelial Growth Factor A / chemistry
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Glycosaminoglycans
  • Immobilized Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Hyaluronic Acid
  • Chondroitin Sulfates
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2