Characterization of kringle domains of angiostatin as antagonists of endothelial cell migration, an important process in angiogenesis

Citation
Wdr. Ji et al., Characterization of kringle domains of angiostatin as antagonists of endothelial cell migration, an important process in angiogenesis, FASEB J, 12(15), 1998, pp. 1731-1738
Citations number
46
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Experimental Biology
Journal title
FASEB JOURNAL
ISSN journal
0892-6638 → ACNP
Volume
12
Issue
15
Year of publication
1998
Pages
1731 - 1738
Database
ISI
SICI code
0892-6638(199812)12:15<1731:COKDOA>2.0.ZU;2-A
Abstract
Angiogenesis is a complex process that involves endothelial cell proliferat ion, migration, basement membrane degradation, and neovessel organization. Angiostatin, consisting of four homologous triple-disulfide bridged kringle domains, has previously been shown to exhibit profound inhibition of endot helial cell proliferation in vitro and angiogenesis in vivo. It was also de monstrated that angiostatin could suppress the growth of a variety of tumor s via the blocking of angiogenesis. The primary aim of our study was to cha racterize the kringle domains of angiostatin for their inhibitory activitie s of endothelial cell migration in order to elucidate their contributions t o the anti-angiogenic function of angiostatin. In this report, we demonstra te for the first time that the kringles of angiostatin play different roles in inhibiting endothelial cell migration, a crucial process in angiogenesi s. Kringle 4, which has only marginal anti-proliferative activity, is among the most potent fragments in inhibiting endothelial cell. migration (IC50 Of approximately 500 nM). In contrast, kringle 1-3, which is equivalent to angiostatin in inhibiting endothelial cell proliferation, manifests only a modest anti-migratory effect. The combination of kringle 1-3 and kringle 4 results in an anti-migratory activity comparable to that of angiostatin. Wh en kringle 1 is removed from kringle 1-3, the resulting kringle 2-3 becomes more potent than kringle 1-3. This implies that kringle 1, although virtua lly ineffective in inhibiting endothelial cell migration, may influence the conformation of kringle 1-3 to alter its anti-migratory activity. We also show that disruption of the kringle structure by reducing/alkylating agents markedly attenuates the anti-migratory activity of angiostatin, demonstrat ing the significance of kringle conformation in maintaining the anti-angiog enic activity of angiostatin. Our data suggest that different kringle domai ns may contribute to the overall anti-angiogenic function of angiostatin by their distinct anti-migratory activities.