Plasmin-induced migration of endothelial cells. A potential target for the anti-angiogenic action of angiostatin.
Angiostatin, a plasminogen fragment containing 3-4 N-terminal kringle domains, is a potent inhibitor of tumor-induced angiogenesis, but its mechanism of action is unclear. Angiostatin is a ligand for integrin alphavbeta(3) but does not induce stress fiber formation upon integrin binding, suggesting that angiostatin is a potential integrin antagonist. Plasmin, the parent molecule of angiostatin and a major extracellular protease, induces platelet aggregation, migration of peripheral blood monocytes, and release of arachidonate and leukotriene from several cell types. In the current study, we found that plasmin specifically bound to alphavbeta(3) through the kringle domains and induced migration of endothelial cells. In contrast, angiostatin did not induce cell migration. Notably, angiostatin, anti-alphavbeta(3) antibodies, RGD-peptide, and a serine protease inhibitor effectively blocked plasmin-induced cell migration. These results suggest that plasmin-induced migration of endothelial cells requires alphavbeta(3) and the catalytic activity of plasmin and that this process is a potential target for the inhibitory activity of angiostatin.
Tarui
Takehiko
T
Department of Cell Biology, VB-6, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Majumdar
Mousumi
M
Miles
Lindsey A
LA
Ruf
Wolfram
W
Takada
Yoshikazu
Y
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins; D000818:Animals; D016466:CHO Cells; D020134:Catalytic Domain; D002465:Cell Movement / Q000187:drug effects; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005341:Fibrinolysin / Q000737:chemistry / Q000494:pharmacology*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010958:Plasminogen / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen; D005341:Fibrinolysin