Angiostatin antagonizes the action of VEGF-A in human endothelial cells via two distinct pathways

Ya Huey Chen, Hua Lin Wu, Chi Kwan Chen, Ya Hui Huang, Bei Chang Yang, Li Wha Wu

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Angiostatin consisting of the first four-kringle domains of the plasminogen potently inhibits angiogenesis in vitro and in vivo. However, the molecular mechanism of action whereby angiostatin mediates its inhibitory effect on proliferating endothelial cells remains elusive. We therefore used the proliferating cultured human umbilical vein endothelial cells (HUVECs) promoted by vascular endothelial growth factor A to identify the endogenous signaling elements that mediate the antiangiogenic effect of angiostatin. Treatment of HUVEC with angiostatin at a concentration known to inhibit cell proliferation and induce apoptosis resulted in induction of p53-, Bax-, and tBid-mediated release of cytochrome c into the cytosol. In addition, angiostatin also activated the Fas-mediated apoptotic pathway in part via up-regulation of FasL mRNA, down-regulation of c-Flip, and activation of caspase 3. These results suggest that the anti-angiogenic action of angiostatin is likely mediated by two distinct signaling pathways, one intrinsic mediated by p53 while the other extrinsic involved in FasL engagement and mitochondria dysfunction.

Original languageEnglish
Pages (from-to)804-810
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume310
Issue number3
DOIs
Publication statusPublished - 2003 Oct 24

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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