Alginate Sulfates Mitigate Binding Kinetics of Proangiogenic Growth Factors with Receptors toward Revascularization.

Abstract

Ever since proangiogenic growth factors have been used as a vascular medicine to treat tissue ischemia, efforts have been increasingly made to develop a method to enhance efficacy of growth factors in recreating microvascular networks, especially at low dose. To this end, we hypothesized that polysaccharides substituted with sulfate groups would amplify growth factor receptor activation and stimulate phenotypic activities of endothelial cells involved in neovascularization. We examined this hypothesis by modifying alginate with a controlled number of sulfates and using it to derive a complex with vascular endothelial growth factor (VEGF), as confirmed with fluorescence resonance energy transfer (FRET) assay. Compared with the bare VEGF and with a mixture of VEGF and unmodified alginates, the VEGF complexed with alginate sulfates significantly reduced the dissociation rate with the VEGFR-2, elevated VEGFR-2 phosphorylation level, and increased the number of endothelial sprouts in vitro. Furthermore, the VEGF-alginate sulfate complex improved recovery of perfusion in an ischemic hindlimb of a mouse due to the increase of the capillary density. Overall, this study not only demonstrates an important cofactor of VEGF but also uncovers an underlying mechanism by which the cofactor mitigates the VEGF-induced signaling involved in the binding kinetics and activation of VEGFR. We therefore believe that the results of this study will be highly useful in improving the therapeutic efficacy of various growth factors and expediting their uses in clinical treatments of wounds and tissue defects.

• Authors: John Schmidt, Min Kyung Lee, Eunkyung Ko, Jae Hyun Jeong, Luisa A DiPietro, Hyunjoon Kong
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 13 Issue 7 Pg. 2148-54 (07 05 2016) ISSN: 1543-8392 [Electronic] United States
• PMID: 26881299 (Publication Type: Journal Article)

Chemical References

• Alginates
• Hexuronic Acids
• Sulfates
• Vascular Endothelial Growth Factor A
• Glucuronic Acid
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Alginates (pharmacology)
• Animals
• Capillaries (drug effects)
• Cells, Cultured
• Glucuronic Acid (pharmacology)
• Hexuronic Acids (pharmacology)
• Hindlimb (drug effects, metabolism)
• Human Umbilical Vein Endothelial Cells
• Humans
• Ischemia (drug therapy, metabolism)
• Kinetics
• Mice
• Mice, Inbred C57BL
• Mice, SCID
• Neovascularization, Pathologic (drug therapy, metabolism)
• Sulfates (pharmacology)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)