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J. Biol. Chem., Vol. 275, Issue 25, 18615-18618, June 23, 2000

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Agkistin, a Snake Venom-derived Glycoprotein Ib Antagonist, Disrupts von Willebrand Factor-Endothelial Cell Interaction and Inhibits Angiogenesis^*

Chia-Hsin Yeh, Wen-Cheng Wang, Tsang-Tang Hsieh^§, and Tur-Fu Huang^¶

From the  Department of Pharmacology, College of Medicine, National Taiwan University and ^§ Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei 100, Taiwan

Glycoprotein (GP) Ib, an adhesion receptor expressed on both platelets and endothelial cells, mediates the binding of von Willebrand factor (vWF). Platelet GPIb plays an important role in platelet adhesion and activation, whereas the interaction of vWF and endothelial GPIb is not fully understood. We report here that agkistin, a snake venom protein, selectively blocks the interaction of vWF with human endothelial GPIb and inhibits angiogenesis in vivo. Agkistin specifically blocked human umbilical vein endothelial cell (HUVEC) adhesion to immobilized vWF in a concentration-dependent manner. Fluorescein isothiocyanate (FITC)-conjugated agkistin bound to HUVECs in a saturable manner. AP1, a monoclonal antibody (mAb) raised against GPIb, specifically inhibited the binding of FITC-conjugated agkistin to HUVECs in a dose-dependent manner, but other anti-integrin mAbs raised against _v3, ₂₁, and ₅₁ did not affect this binding reaction. However, neither agkistin (2 µg/ml) nor AP1 (40 µg/ml) apparently reduced HUVEC viability. Both agkistin and AP1 exhibited a profound anti-angiogenic effect in vivo when assayed by using the 10-day-old embryo chick chorioallantoic membrane model. These results suggest endothelial GPIb plays a role in spontaneous angiogenesis in vivo, and the anti-angiogenic effect of agkistin may be because of disruption of the interaction of endogenous vWF with endothelial GPIb.

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