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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4730-4741
Multiple Forms of Angiostatin Induce Apoptosis in Endothelial Cells
R. Lucas,
L. Holmgren,
I. Garcia,
B. Jimenez,
S.J. Mandriota,
F. Borlat,
B.K.L. Sim,
Z. Wu,
G.E. Grau,
Y. Shing,
G.A. Soff,
N. Bouck, and
M.S. Pepper
From the Laboratory of Immunopathology and Laboratory of Intensive
Care, Department of Anesthesiology, Pharmacology, and Surgical
Intensive Care, and Department of Internal Medicine, Geneva University
Hospital, Geneva, Switzerland; the Center for Genomics Research,
Karolinska Institute, Stockholm, Sweden; the Departments of Pathology
and of Morphology, University Medical Center, Geneva, Switzerland; the
Department of Microbiology-Immunology, Division of Hematology-Oncology,
and R.H. Lurie Cancer Center, Northwestern University Medical School,
Chicago, IL; the Serono Pharmaceutical Research Institute S.A., Geneva,
Switzerland; EntreMed Inc, Rockville, MD; and the Department of
Surgical Research, Children's Hospital, Harvard Medical School,
Boston, MA.
Angiostatin is a circulating inhibitor of angiogenesis generated by
proteolytic cleavage of plasminogen. In this study we have used
recombinant human and murine angiostatins (kringles 1-4) as well as
native human angiostatin (prepared by elastase digestion of plasminogen
[kringles 1-3] or by plasmin autocatalysis in the presence of a free
sulfhydryl donor [kringles 1-4]). We report that angiostatin reduces
endothelial cell number in a 4-day proliferation assay without
affecting cell cycle progression into S-phase (as determined by
bromodeoxyuridine labeling). This suggested that the reduction in cell
number in the proliferation assay might in part be due to cytotoxicity.
This was confirmed by the observation that ethidium homodimer
incorporation (a measure of plasma membrane integrity) into endothelial
cells was increased by angiostatin in a manner similar to that seen
with tumor necrosis factor- (TNF-) and transforming growth
factor- 1 (TGF-1), both of which induce apoptosis in endothelial
cells. In contrast to TNF- and TGF-1, angiostatin did not induce
cytotoxicity in human MRC-5 fibroblast, rat smooth muscle, canine MDCK
epithelial, or murine B16-F10 melanoma cell lines. Angiostatin-induced
apoptosis was confirmed by endothelial cell nuclear acridine orange
incorporation as well as by annexin V and TUNEL staining. These in
vitro findings point to endothelial cell apoptosis as a mechanism for
the antiangiogenic effect of angiostatin in vivo.
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