Augmentation of vascular permeability of VEGF is enhanced by KDR-binding proteins.
VEGF165 is a key regulator of angiogenesis and a potent vascular permeability factor. Using snake venom proteins as tools, we demonstrate the enhanced vascular leakage of VEGF by KDR-binding proteins. The snake venom-derived KDR-specific VEGF, vammin, potently enhanced vascular leakage compared with other known permeability-enhancing factors including VEGF165, while KDR-bp from snake venom, a KDR antagonist of endothelial cell growth was a very weak permeability enhancer. Unexpectedly when co-administrated, KDR-bp synergistically enhanced either vammin or VEGF165-stimulated vascular leakage, despite its antagonistic effect on cell growth. This augmenting effect was specifically observed in the combined administration of KDR-bp with either VEGF165 or vammin, but not other combination of known permeability-enhancing factors. We further demonstrated a similar increased vascular leakage by the combined administration of VEGF165 and TIMP-3, the only known endogenous antagonist of KDR. Our findings implicate TIMP-3 as a critical player in the vascular leakage-enhancing effect of VEGF165 in vivo.
Yamazaki
Yasuo
Y
Department of Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
Nakano
Yuta
Y
Imamura
Takahisa
T
Morita
Takashi
T
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D004357:Drug Synergism; D054501:Group II Phospholipases A2; D006168:Guinea Pigs; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D030162:Reptilian Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D014757:Viper Venoms / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D030162:Reptilian Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A; D014757:Viper Venoms; C519402:vammin protein, Vipera ammodytes ammodytes; D010741:Phospholipases A; D054501:Group II Phospholipases A2; C504244:KDR-binding protein, Agkistrodon piscivorus