VASCULAR BIOLOGY Nicked 2-glycoprotein I binds angiostatin 4.5 (plasminogen kringle 1-5) and attenuates its antiangiogenic property

Angiostatin was first discovered as a plasminogen fragment with antitumor/antiangiogenic property. One of the angiostatin isoforms, that is, angiostatin 4.5 (AS4.5), consisting of plasminogen kringle 1 to 4 and a most part of kringle 5, is produced by autoproteolysis and present in human plasma. 2-glycoprotein I ( 2GPI) is proteolytically cleaved by plasmin in its domain V (nicked 2GPI), resulting in binding to plasminogen. Antiangiogenic properties have been recently reported in nicked 2GPI as well as in intact 2GPI at higher concentrations. In the present study, we found significant binding of nicked 2GPI to AS4.5 (KD 3.27 106 M 1). Via this binding, nicked 2GPI attenuates the antiangiogenic functions of AS4.5 in the proliferation of arterial/venous endothelial cells, in the extracellular matrix invasion and the tube formation of venous endothelial cells, and in vivo angiogenesis. In contrast, intact 2GPI does not bind toAS4.5 or inhibit its antiangiogenic activity. Thus, nicked 2GPI exerts dual effects on angiogenesis, that is, nicked 2GPI promotes angiogenesis in the presence of AS4.5, whereas nicked 2GPI inhibits angiogenesis at concentrations high enough to neutralize AS4.5. Our data suggest that plasmin-nicked 2GPI promotes angiogenesis by interacting with plasmin-generated AS4.5 in sites of increased fibrinolysis such as thrombus. (Blood. 2009;114:2553-2559)