Angiostatin4.5-mediated apoptosis of vascular endothelial cells

Holly Anne Hanford, Christie A. Wong, Hallie Kassan, Deborah L. Cundiff, Navdeep Chandel, Suzanne Underwood, Christopher A. Mitchell, Gerald A. Soff*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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 angiostatin4.5, 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 antgiostatin4.5-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 angiostatin4.5. 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 angiostatin4.5 treatment. Angiostatin4.5 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.

Original languageEnglish (US)
Pages (from-to)4275-4280
Number of pages6
JournalCancer Research
Volume63
Issue number14
StatePublished - Jul 15 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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