NFκ-B balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement

NFκ-B balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement

A B Aurora, D Biyashev, Y Mirochnik, T A Zaichuk, C Sánchez-Martinez, M A Renault, D Losordo and O V Volpert

Blood First Edition Paper, prepublished online March 4, 2010; doi: 10.1182/blood-2009-07-232132.


Extracellular factors control the angiogenic switch in endothelial cells (EC) via competing survival and apoptotic pathways. Previously, we showed that pro- and anti-angiogenic factors target the same signaling molecules, which thereby become pivots of angiogenic balance. Here we show that in remodeling endothelium (EC and EC precursors) natural angiogenic inhibitors enhance NFκB DNA binding that is critical for anti-angiogenesis; blocking the NFκB pathway abolished multiple anti-angiogenic events in vitro and in vivo. NFκB induction by anti-angiogenic molecules has a dual effect on transcription. NFκB acts as an activator of pro-apoptotic FasL and as a repressor of pro-survival cFLIP. On the FasL promoter, NFκB increases the recruitment of HAT p300, and acetylated histones H3 and H4. Conversely, on cFLIP promoter, NFκB increases 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 PEDF 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.

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