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Yvette van Hensbergen, Henk J. Broxterman, Erna Peters, Sareena Rana, Yvonne W. Elderkamp, Victor W. M. van Hinsbergh, Pieter Koolwijk
Aminopeptidase inhibitor bestatin stimulates microvascular endothelial cell invasion in a fibrin matrix
The aminopeptidase inhibitor bestatin has been shown to have anti-angiogenic effects in a number of model systems. These effects are thought to result from inhibition of CD13 activity. Because tumor angiogenesis can evolve in a fibrin-rich stroma matrix we have studied for the first time the effects of bestatin on microvascular endothelial capillary-like tube formation in a fibrin matrix. Bestatin enhanced the formation of capillary-like tubes dose-dependently. Its effects were apparent at 8 M; the increase was 3.7-fold at 125 M; while high concentrations (>250 M), that were shown to have anti-angiogenic effects in other systems, caused extensive matrix degradation. Specific CD13-blocking antibodies WM15 and MY-7, and the aminopeptidase inhibitors amastatin and actinonin also enhanced capillary-like tube formation (maximally 1.5-fold), but these effects did not reach statistical significance. The effect of bestatin was not due to a change in uPAR availability because the relative involvement of the u-PA/u-PAR activity was not altered by bestatin. In view of the present findings we hypothesize that aminopeptidases other than CD13 predominantly contribute to the observed pro-angiogenic effect of bestatin in a fibrin matrix. The identification of this novel effect of bestatin is important in the light of the proposed use of bestatin as anti-angiogenic and/or anti-tumor agent.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 90, 11/2003
Pages: 921 - 929