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NF-kappaB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement

Arin B Aurora1, Aryn B Aurora, Dauren Biyashev

  • 1Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Blood
|March 6, 2010
PubMed

Insights

Natural angiogenic inhibitors enhance nuclear factor-kappaB (NF-kappaB) DNA binding, crucial for antiangiogenesis. Blocking this pathway disrupts antiangiogenic events, offering new therapeutic strategies for controlling blood vessel formation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Extracellular factors regulate endothelial cell (EC) survival and apoptosis, controlling the angiogenic switch.
  • Proangiogenic and antiangiogenic factors converge on shared signaling molecules, influencing angiogenic balance.
  • The nuclear factor-kappaB (NF-kappaB) pathway plays a critical role in regulating angiogenesis.

Purpose of the Study:

  • To investigate the role of NF-kappaB in antiangiogenesis mediated by natural inhibitors.
  • To elucidate the transcriptional mechanisms by which NF-kappaB regulates proapoptotic and prosurvival factors.
  • To explore the potential of histone deacetylase inhibitors (HDACi) in modulating the angiogenic switch.

Main Methods:

  • Assessed NF-kappaB DNA binding in remodeling endothelium.
  • Investigated the effect of blocking the NF-kappaB pathway on antiangiogenic events in vitro and in vivo.
  • Analyzed NF-kappaB's transcriptional regulation of FasL and cFLIP promoters.
  • Examined the impact of HDAC inhibitors on pigment epithelial-derived factor activity and histone acetylation.

Main Results:

  • Natural angiogenic inhibitors enhance NF-kappaB DNA binding, essential for antiangiogenesis.
  • Blocking NF-kappaB abrogates multiple in vitro and in vivo antiangiogenic effects.
  • NF-kappaB activates proapoptotic FasL transcription by increasing HAT p300 and histone acetylation.
  • NF-kappaB represses prosurvival cFLIP transcription by increasing HDAC1 and decreasing histone acetylation.
  • HDAC inhibitors exhibit a dose-dependent biphasic effect on pigment epithelial-derived factor activity.

Conclusions:

  • A complex transcriptional network governs angiogenic balance, involving NF-kappaB-mediated regulation of key apoptotic and survival genes.
  • Targeting the NF-kappaB pathway and histone acetylation presents a viable strategy for manipulating the angiogenic switch.
  • HDAC inhibitors show promise as therapeutic tools for controlling angiogenesis.

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