TY - JOUR
T1 - Vascular Endothelial Growth Factor 165 (VEGF165) Activities Are Inhibited by Carboxymethyl Benzylamide Dextran that Competes for Heparin Binding to VEGF165 and VEGF165·KDR Complexes
AU - Hamma-Kourbali, Yamina
AU - Vassy, Roger
AU - Starzec, Anna
AU - Le Meuth-Metzinger, Valérie
AU - Oudar, Olivier
AU - Bagheri-Yarmand, Rozita
AU - Perret, Gérard
AU - Crépin, Michel
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2001/10/26
Y1 - 2001/10/26
N2 - We have previously shown that carboxymethyl dextran benzylamide (CMDB7), a heparin-like molecule, inhibits the growth of tumors xenografted in nude mice, angiogenesis, and metastasis by altering the binding of angiogenic growth factors, including platelet-derived growth factor, transforming growth factor β, and fibroblast growth factor 2, to their specific receptors. In this study, we explore the effect of CMDB7 on the most specific angiogenic growth factor, vascular endothelial growth factor 165 (VEGF165). We demonstrate here that CMDB7 inhibits the mitogenic effect of VEGF165 on human umbilical vein endothelial cells (HUV-ECs) by preventing the VEGF 165-induced VEGF receptor-2 (KDR) autophosphorylation and consequently a specific intracellular signaling. In competition experiments, the binding of 125I-VEGF165 to HUV-ECs is inhibited by CMDB7 with an IC50 of 2 μM. Accordingly, CMDB7 inhibits the cross-linking of 125I-VEGF165 to the surface of HUV-ECs, causing the disappearance of both labeled complexes, 170-180 and 240-250 kDa. We show that CMDB7 increases the electrophoretic mobility of VEGF 165, thus evidencing formation of a stable complex with this factor. Moreover, CMDB7 reduces the 125I-VEGF165 binding to coated heparin-albumin and prevents a heparin-induced increase in iodinated VEGF165 binding to soluble 125I-KDR-Fc chimera. Concerning KDR, CMDB7 has no effect on 125I-KDR-Fc electrophoretic migration and does not affect labeled KDR-Fc binding to coated heparin-albumin. In the presence of VEGF165, 125I-KDR-Fc binding to heparin is enhanced, and under these conditions, CMDB7 interferes with KDR binding. These data indicate that CMDB7 effectively inhibits the VEGF 165 activities by interfering with heparin binding to VEGF 165 and VEGF165·KDR complexes but not by direct interactions with KDR.
AB - We have previously shown that carboxymethyl dextran benzylamide (CMDB7), a heparin-like molecule, inhibits the growth of tumors xenografted in nude mice, angiogenesis, and metastasis by altering the binding of angiogenic growth factors, including platelet-derived growth factor, transforming growth factor β, and fibroblast growth factor 2, to their specific receptors. In this study, we explore the effect of CMDB7 on the most specific angiogenic growth factor, vascular endothelial growth factor 165 (VEGF165). We demonstrate here that CMDB7 inhibits the mitogenic effect of VEGF165 on human umbilical vein endothelial cells (HUV-ECs) by preventing the VEGF 165-induced VEGF receptor-2 (KDR) autophosphorylation and consequently a specific intracellular signaling. In competition experiments, the binding of 125I-VEGF165 to HUV-ECs is inhibited by CMDB7 with an IC50 of 2 μM. Accordingly, CMDB7 inhibits the cross-linking of 125I-VEGF165 to the surface of HUV-ECs, causing the disappearance of both labeled complexes, 170-180 and 240-250 kDa. We show that CMDB7 increases the electrophoretic mobility of VEGF 165, thus evidencing formation of a stable complex with this factor. Moreover, CMDB7 reduces the 125I-VEGF165 binding to coated heparin-albumin and prevents a heparin-induced increase in iodinated VEGF165 binding to soluble 125I-KDR-Fc chimera. Concerning KDR, CMDB7 has no effect on 125I-KDR-Fc electrophoretic migration and does not affect labeled KDR-Fc binding to coated heparin-albumin. In the presence of VEGF165, 125I-KDR-Fc binding to heparin is enhanced, and under these conditions, CMDB7 interferes with KDR binding. These data indicate that CMDB7 effectively inhibits the VEGF 165 activities by interfering with heparin binding to VEGF 165 and VEGF165·KDR complexes but not by direct interactions with KDR.
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U2 - 10.1074/jbc.M101117200
DO - 10.1074/jbc.M101117200
M3 - Article
C2 - 11514538
AN - SCOPUS:0035955644
SN - 0021-9258
VL - 276
SP - 39748
EP - 39754
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -