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

[摘要]：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. beta 2-glycoprotein I (beta 2GPI) is proteolytically cleaved by plasmin in its domain V (nicked beta 2GPI), resulting in binding to plasminogen. Antiangiogenic properties have been recently reported in nicked beta 2GPI as well as in intact beta 2GPI at higher concentrations. In the present study, we found significant binding of nicked beta 2GPI to AS4.5 (K-D = 3.27 x 10(6) M-1). Via this binding, nicked beta 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 beta 2GPI does not bind to AS4.5 or inhibit its antiangiogenic activity. Thus, nicked beta 2GPI exerts dual effects on angiogenesis, that is, nicked beta 2GPI promotes angiogenesis in the presence of AS4.5, whereas nicked beta 2GPI inhibits angiogenesis at concentrations high enough to neutralize AS4.5. Our data suggest that plasmin-nicked beta 2GPI promotes angiogenesis by interacting with plasmin-generated AS4.5 in sites of increased fibrinolysis such as thrombus. (Blood. 2009; 114: 2553-2559)

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