1. Aminopeptidase inhibitor bestatin stimulates microvascular endothelial cell invasion in a fibrin matrix
- Author
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Yvette van Hensbergen, Sareena Rana, Victor W.M. van Hinsbergh, Erna Peters, Pieter Koolwijk, Henk J. Broxterman, Yvonne W. Elderkamp, VU University medical center, and Gaubius Instituut TNO
- Subjects
Integrins ,Umbilical Veins ,Biomedical Research ,Angiogenesis ,Bestatin ,urokinase ,Aminopeptidase ,Aminopeptidases ,amastatin ,chemistry.chemical_compound ,angiogenesis ,Cell Movement ,antibody ,dose response ,endothelium cell ,Actinonin ,antineoplastic agent ,Cells, Cultured ,Tube formation ,actinonin ,WM15 antibody ,drug effect ,Hematology ,cell invasion ,Cell biology ,unclassified drug ,enzyme activity ,Endothelial stem cell ,Vascular endothelial growth factor A ,Biochemistry ,priority journal ,u-PAR ,Urinary Plasminogen Activator ,hypothesis ,vascular endothelium ,tumor ,enzyme inhibitor ,Antigens, CD13 ,Neovascularization, Physiologic ,Ubenimex ,Receptors, Cell Surface ,Biology ,CD13 Antigens ,Receptors, Urokinase Plasminogen Activator ,Amastatin ,Leucine ,urokinase receptor ,stroma ,Humans ,controlled study ,protein expression ,microsomal aminopeptidase ,Fibrin ,concentration (parameters) ,Dose-Response Relationship, Drug ,MY 7 antibody ,vasculotropin ,human cell ,Microcirculation ,basic fibroblast growth factor ,Urokinase-Type Plasminogen Activator ,chemistry ,Endothelium, Vascular - Abstract
SummaryThe 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.
- Published
- 2003