Bactericidal/permeability-increasing protein (BPI) inhibits angiogenesis via induction of apoptosis in vascular endothelial cells

Abstract

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-μM 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 μmol/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.

A murine antibacterial ortholog to human bactericidal/permeability-increasing protein (BPI) is expressed in testis, epididymis, and bone marrow

“…Hence, antimicrobial proteins can have other specific properties when expressed in various tissues. Indeed, BPI has been implicated in biological functions besides those related directly to bactericidal effects, e.g., to act as an endogenous inhibitor of angiogenesis [43], to neutralize the inflammatory effects of LPS [44], or to stimulate phagocytosis by complement activation [45]. The present identification of mouse BPI opens the possibility to investigate its physiological and pathophysiological role in vivo by elimination of the gene in transgenic mice.…”

Effects of major liver resection, with or without recombinant bactericidal/permeability‐increasing protein (rBPI21), on the angiogenic profile of patients with metastatic colorectal carcinoma

“…After 24-hr continuous rBPI 21 administration, VEGF levels are significantly higher when compared to the control group on day þ1. This observation may be explained by the competition of rBPI 21 with locally generated VEGF on heparin binding sites in the extracellular matrix (ECM), resulting in less storage of VEGF during rBPI 21 infusion [9,12]. This may alter a VEGF concentration gradient that is required for guided EC migration, confirming the idea of antiangiogenic effects of rBPI 21 .…”

“…Angiogenesis is regulated by a number of specific stimulators and inhibitors. A recent study showed that BPI also functions as an angiogenic inhibitor [9]. Therefore, we were interested in the effects of rBPI on angiogenic parameters after liver surgery.…”

Vascular targeting effect of combretastatin A‐4 phosphate dominates the inherent angiogenesis inhibitory activity

“…Sprouting and tube formation were studied with the use of cytodex-3 beads overgrown with BCE in a three-dimensional (3D) gel as described. 25 Beads overgrown with EC were resuspended in vitrogen-100 gel (Collagen, Fremont, CA). After gelation, 50 l medium was applied on top of the gel containing 20 ng/ml bFGF with or without combreAp at concentrations as indicated.…”