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

Blood. 2010 Jul 22;116(3):475-84. doi: 10.1182/blood-2009-07-232132. Epub 2010 Mar 4.


Extracellular factors control the angiogenic switch in endothelial cells (ECs) via competing survival and apoptotic pathways. Previously, we showed that proangiogenic and antiangiogenic factors target the same signaling molecules, which thereby become pivots of angiogenic balance. Here we show that in remodeling endothelium (ECs and EC precursors) natural angiogenic inhibitors enhance nuclear factor-kappaB (NF-kappaB) DNA binding, which is critical for antiangiogenesis, and that blocking the NF-kappaB pathway abolishes multiple antiangiogenic events in vitro and in vivo. NF-kappaB induction by antiangiogenic molecules has a dual effect on transcription. NF-kappaB acts as an activator of proapoptotic FasL and as a repressor of prosurvival cFLIP. On the FasL promoter, NF-kappaB increases the recruitment of HAT p300 and acetylated histones H3 and H4. Conversely, on cFLIP promoter, NF-kappaB increases histone deacetylase 1 (HDAC1), decreases p300 and histone acetylation, and reduces the recruitment of NFAT, a transcription factor critical for cFLIP expression. Finally, we found a biphasic effect, when HDAC inhibitors (HDACi) were used to test the dependence of pigment epithelial-derived factor activity on histone acetylation. The cooperative effect seen at low doses switches to antagonistic as the concentrations increase. Our study defines an interactive transcriptional network underlying angiogenic balance and points to HDACi as tools to manipulate the angiogenic switch.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • Chromatin Assembly and Disassembly / physiology*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Eye Proteins / pharmacology
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism
  • Female
  • Histone Deacetylase 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • NF-kappa B / physiology*
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / physiology*
  • Neovascularization, Physiologic* / drug effects
  • Neovascularization, Physiologic* / genetics
  • Nerve Growth Factors / pharmacology
  • Promoter Regions, Genetic
  • Serpins / pharmacology
  • Signal Transduction
  • Thrombospondin 1 / pharmacology


  • Angiogenesis Inhibitors
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Eye Proteins
  • Fas Ligand Protein
  • Fasl protein, mouse
  • NF-kappa B
  • NFATC Transcription Factors
  • Nerve Growth Factors
  • Nfatc2 protein, mouse
  • Serpins
  • Thrombospondin 1
  • pigment epithelium-derived factor
  • Hdac1 protein, mouse
  • Histone Deacetylase 1