Bactericidal/permeability-increasing protein (BPI) inhibits angiogenesis via induction of apoptosis in vascular endothelial cells.
Bactericidal/permeability-increasing protein (BPI) has been known for some time to function in killing bacteria and in neutralizing the effects of bacterial endotoxin lipopolysaccharide. In the present study, BPI is found to be a novel endogenous inhibitor of angiogenesis. Within the sub-muM range, BPI shows a concentration-dependent inhibition of endothelial cell (EC) proliferation that is mediated by cell detachment and subsequent induction of apoptosis. As measured by flow cytometric analysis of the percentage of subdiploid cells, apoptosis induction was half-maximal at about 250 nmol/L BPI. Apoptosis was confirmed by quantification of cells with nuclear fragmentation. Apoptosis was found to be EC specific. In an in vitro collagen gel-based angiogenesis assay, BPI at 1.8 micromol/L inhibited tube formation by 81% after only 24 hours. Evidence for in vivo inhibition of angiogenesis was obtained, using the chorioallantoic membrane assay in which BPI was seen to be significantly effective at concentrations as low as 180 nmol/L. This newly discovered function of BPI might provide a possible therapeutic modality for the treatment of various pathologic disorders that depend on angiogenesis.
van der Schaft
D W
DW
Tumor Angiogenesis Laboratory, Department of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands. DvdSchaft@hotmail.com
Toebes
E A
EA
Haseman
J R
JR
Mayo
K H
KH
Griffioen
A W
AW
D000482:Allantois / Q000098:blood supply; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D053938:DNA Fragmentation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D004912:Erythrocytes / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D008565:Membrane Proteins; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D014471:Umbilical Veins
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D008565:Membrane Proteins; C021623:bactericidal permeability increasing protein; D016222:Fibroblast Growth Factor 2; D006493:Heparin