TY - JOUR
T1 - NF-κB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement
AU - Aurora, Aryn B.
AU - Biyashev, Dauren
AU - Mirochnik, Yelena
AU - Zaichuk, Tetiana A.
AU - Sánchez-Martinez, Cristina
AU - Renault, Marie Ange
AU - Losordo, Douglas
AU - Volpert, Olga V.
PY - 2010/7/22
Y1 - 2010/7/22
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2009-07-232132
DO - 10.1182/blood-2009-07-232132
M3 - Article
C2 - 20203265
AN - SCOPUS:77955916842
SN - 0006-4971
VL - 116
SP - 475
EP - 484
JO - Blood
JF - Blood
IS - 3
ER -