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

Aryn B. Aurora, Dauren Biyashev, Yelena Mirochnik, Tetiana A. Zaichuk, Cristina Sánchez-Martinez, Marie Ange Renault, Douglas Losordo, Olga V. Volpert

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

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-κB (NF-κB) DNA binding, which is critical for antiangiogenesis, and that blocking the NF-κB pathway abolishes multiple antiangiogenic events invitro and in vivo. NF-κB induction by antiangiogenic molecules has a dual effect on transcription. NF-κB acts as an activator of proapoptotic FasL and as a repressor of prosurvival cFLIP. On the FasL promoter, NF-κB increases the recruitment of HAT p300 and acetylated histones H3 and H4. Conversely, on cFLIP promoter, NF-κB 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.

Original languageEnglish (US)
Pages (from-to)475-484
Number of pages10
JournalBlood
Volume116
Issue number3
DOIs
StatePublished - Jul 22 2010

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Aurora, A. B., Biyashev, D., Mirochnik, Y., Zaichuk, T. A., Sánchez-Martinez, C., Renault, M. A., Losordo, D., & Volpert, O. V. (2010). NF-κB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement. Blood, 116(3), 475-484. https://doi.org/10.1182/blood-2009-07-232132