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

Ya-Huey Chen1, Hua-Lin Wu, Chi-Kwan Chen

  • 1Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.

Biochemical and Biophysical Research Communications
|October 11, 2003
PubMed

Insights

Angiostatin inhibits angiogenesis by triggering programmed cell death in endothelial cells. It activates both intrinsic (p53-mediated) and extrinsic (FasL-mediated) apoptotic pathways, leading to cell death and reduced blood vessel formation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Angiostatin, derived from plasminogen, is a potent inhibitor of angiogenesis.
  • The precise molecular mechanisms underlying angiostatin's anti-angiogenic effects on endothelial cells are not fully understood.

Purpose of the Study:

  • To elucidate the endogenous signaling pathways involved in angiostatin's anti-angiogenic activity.
  • To identify the specific molecular players mediating angiostatin's effects on human umbilical vein endothelial cells (HUVECs).

Main Methods:

  • Utilized cultured HUVECs stimulated with vascular endothelial growth factor A (VEGF-A).
  • Investigated the impact of angiostatin treatment on apoptotic signaling pathways.
  • Analyzed the expression of key proteins and mRNA involved in intrinsic and extrinsic apoptosis.

Main Results:

  • Angiostatin induced apoptosis in HUVECs via both intrinsic (p53, Bax, tBid, cytochrome c release) and extrinsic (FasL, caspase 3 activation, c-Flip down-regulation) pathways.
  • Angiostatin treatment led to mitochondrial dysfunction and activation of the Fas-mediated apoptotic cascade.
  • Specific molecular mediators of angiostatin's anti-angiogenic action were identified.

Conclusions:

  • Angiostatin's anti-angiogenic effect is mediated through a dual signaling mechanism involving intrinsic and extrinsic apoptotic pathways.
  • The intrinsic pathway involves p53 and mitochondrial dysfunction, while the extrinsic pathway engages FasL signaling.
  • These findings provide crucial insights into the molecular basis of angiostatin's therapeutic potential in angiogenesis-related diseases.

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