VARIATIONS IN THE SIZE AND SULFATION OF HEPARIN MODULATE THE EFFECT OF HEPARIN ON THE BINDING OF VEGF(165) TO ITS RECEPTORS

The binding of the 165 amino-acid form of vascular endothelial growth factor (VEGF(165)) 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 I-125-VEGF(165) to VEGF receptors, while fragments larger than 22 sugar units potentiated the binding. Over-sulfated heparin was a better potentiator of I-125-VEGF(165) 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 I-125-VEGF(165) to alpha 2-macroglobulin, but surprisingly, O-desulfated heparin was an ineffective inhibitor. Since alpha 2-macroglobulin does not bind heparin, it follows that VEGF(165) does not bind O-desulfated heparin efficiently. These results suggest that the mechanism by which heparin modulates the binding of VEGF(165) to the VEGF receptors may require an interaction with cell surface heparin binding molecules. (C) 1994 Academic Press, Inc.