Hanford, HA, Wong, CA, Kassan, H, Cundiff, DL, Chandel, N, Underwood, S, Mitchell, Christopher and Soff, GA (2003) Angiostatin(4.5)-mediated apoptosis of vascular endothelial cells. CANCER RESEARCH, 63 (14). pp. 4275-4280. [Journal article]
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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 similar to40% 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 angiostatin4.5. 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 angiostatin4.5 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.
|Item Type:||Journal article|
|Faculties and Schools:||Faculty of Life and Health Sciences|
Faculty of Life and Health Sciences > School of Biomedical Sciences
|Research Institutes and Groups:||Biomedical Sciences Research Institute > Molecular Medicine|
Biomedical Sciences Research Institute > Molecular Medicine > Vascular Medicine
Biomedical Sciences Research Institute
|Deposited By:||Professor Christopher Mitchell|
|Deposited On:||23 Jan 2010 16:04|
|Last Modified:||10 Jun 2010 10:22|
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