Variations in the Size and Sulfation of Heparin Modulate the Effect of Heparin on the Binding of VEGF₁₆₅ to Its Receptors

Abstract

The binding of the 165 amino-acid form of vascular endothelial growth factor (VEGF₁₆₅) to the VEGF receptors of vascular endothelial cells was potentiated by heparin and heparan-sulfate, but not by other glycosaminoglycans. Heparin fragments of 16-18 sugar units inhibited the binding of ¹²⁵I-VEGF₁₆₅ to VEGF receptors, while fragments larger than 22 sugar units potentiated the binding. Over-sulfated heparin was a better potentiator of ¹²⁵I-VEGF₁₆₅ binding than native heparin. O-desulfated and N-desulfated heparins potentiated the binding to a lesser extent than native heparin. Heparin and N-desulfated heparin efficiently inhibited the binding of ¹²⁵I-VEGF₁₆₅ to α2-macroglobulin, but surprisingly, O-desulfated heparin was an ineffective inhibitor. Since α2-macroglobulin does not bind heparin, it follows that VEGF₁₆₅ does not bind O-desulfated heparin efficiently. These results suggest that the mechanism by which heparin modulates the binding of VEGF₁₆₅ to the VEGF receptors may require an interaction with cell surface heparin binding molecules.