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Angiostatin_4.5-mediated Apoptosis of Vascular Endothelial Cells

Northwestern University Feinberg School of Medicine, Department of Medicine, Divisions of Hematology/Oncology [H. A. H., C. A. W., H. K., D. L. C., G. A. S.] and Pulmonary and Critical Care [N. C.], Chicago, Illinois 60611, and Division of Obstetrics and Gynaecology, Nottingham City Hospital, Nottingham, United Kingdom [S. U., C. A. M.]

Angiostatin, a proteolytic cleavage product of plasminogen, acts via a selective, yet poorly understood mechanism to potently inhibit angiogenesis (M. S. O’Reilly et al., Cell, 79: 315–328, 1994). Vascular endothelial cell proliferation assays revealed that angiostatin_4.5, a naturally occurring human isoform consisting of plasminogen kringle domains 1–4 and most of kringle domain 5 (G. A. Soff, Cancer Metastasis Rev., 19: 97–107, 2000), dose dependently reduces cell number despite the presence of a potent stimulus of proliferation. Flow cytometry using the vital dyes Hoechst 33342 and Pyronin Y revealed that 40% of both control and angiostatin_4.5-treated cells were in the proliferative phase, indicating that cell cycle progression is not impaired by exposure to angiostatin_4.5. Both bovine aortic endothelial cells and human umbilical endothelial cells were shown to undergo apoptosis in response to angiostatin_4.5. Caspases-3, -8, and -9 activation, specified by cleavage of fluorophore-conjugated specific peptide substrates, revealed a cascade of caspase activation that peaks at 36 h of angiostatin_4.5 treatment. Angiostatin_4.5 exposure induced release of cytochrome c from mitochondria in a caspase-dependent manner, but a pan-caspase inhibitor, zVAD-fmk, blocked cytochrome c release. Overall, these data indicate that human angiostatin_4.5 may function in vivo to block blood vessel formation by specifically inducing vascular endothelial cells to apoptose in a process likely involving both the intrinsic and extrinsic apoptosis pathways.

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