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 Blood, 17 September 2009, Vol. 114, No. 12, pp. 2553-2559.
Prepublished online as a Blood First Edition Paper on July 22, 2009; DOI 10.1182/blood-2008-12-190629.

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VASCULAR BIOLOGY

Nicked β2-glycoprotein I binds angiostatin 4.5 (plasminogen kringle 1-5) and attenuates its antiangiogenic property

Hisako Nakagawa1, Shinsuke Yasuda1, Eiji Matsuura2, Kazuko Kobayashi2, Masahiro Ieko3, Hiroshi Kataoka1, Tetsuya Horita1, Tatsuya Atsumi1, and Takao Koike1

1 Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo; 2 Department of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama; and 3 Department of Internal Medicine, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan

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. β2-glycoprotein I (β2GPI) is proteolytically cleaved by plasmin in its domain V (nicked β2GPI), resulting in binding to plasminogen. Antiangiogenic properties have been recently reported in nicked β2GPI as well as in intact β2GPI at higher concentrations. In the present study, we found significant binding of nicked β2GPI to AS4.5 (KD = 3.27 x 106 M–1). Via this binding, nicked β2GPI 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 β2GPI does not bind to AS4.5 or inhibit its antiangiogenic activity. Thus, nicked β2GPI exerts dual effects on angiogenesis, that is, nicked β2GPI promotes angiogenesis in the presence of AS4.5, whereas nicked β2GPI inhibits angiogenesis at concentrations high enough to neutralize AS4.5. Our data suggest that plasmin-nicked β2GPI promotes angiogenesis by interacting with plasmin-generated AS4.5 in sites of increased fibrinolysis such as thrombus.


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