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Aminopeptidase inhibitor bestatin stimulates microvascular endothelial cell invasion in a fibrin matrix

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Author: Hensbergen, Y. van · Broxterman, H.J. · Peters, E. · Rana, S. · Elderkamp, Y.W. · Hinsbergh, V.W.M. van · Koolwijk, P.
Type:article
Date:2003
Institution: Gaubius Instituut TNO
Source:Thrombosis and Haemostasis, 5, 90, 921-929
Identifier: 237379
Keywords: Biomedical Research · Angiogenesis · Bestatin · u-PAR · actinonin · amastatin · antibody · antineoplastic agent · basic fibroblast growth factor · enzyme inhibitor · microsomal aminopeptidase · MY 7 antibody · unclassified drug · urokinase · urokinase receptor · vasculotropin · WM15 antibody · angiogenesis · cell invasion · concentration (parameters) · controlled study · dose response · drug effect · endothelium cell · enzyme activity · human cell · hypothesis · priority journal · protein expression · stroma · tumor · vascular endothelium · Aminopeptidases · Antigens, CD13 · Cell Movement · Cells, Cultured · Dose-Response Relationship, Drug · Endothelium, Vascular · Fibrin · Humans · Integrins · Leucine · Microcirculation · Neovascularization, Physiologic · Receptors, Cell Surface · Umbilical Veins · Urinary Plasminogen Activator

Abstract

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 μM; the increase was 3.7-fold at 125 μM; while high concentrations (>250 μM), 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.