NF-κB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement
NF-κB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement
复制标题
DOI：
10.1182/blood-2009-07-232132
复制
发表时间：
2010-07-22
期刊：
影响因子：
20.3
通讯作者：
Volpert, Olga V.
中科院分区：
文献类型：
--
作者：
Aurora, Aryn B.;Biyashev, Dauren;Volpert, Olga V.
细胞外因子通过竞争性存活和凋亡途径控制内皮细胞（EC）中的血管生成开关。以前，我们发现促血管生成和抗血管生成因子靶向相同的信号分子，从而成为血管生成平衡的支点。我们发现在重塑内皮细胞（EC和EC前体）时，天然血管生成抑制剂增强了核因子-κ B（NF-κ B B）DNA结合，这对于抗血管生成至关重要，并且阻断NF-κ B途径在体外和体内抑制了多种抗血管生成事件。抗血管生成分子对NF-κ B的诱导对转录具有双重作用。NF-κ B作为促凋亡FasL的激活剂和作为促存活cFLIP的抑制剂。在FasL启动子上，NF-κ B增加HAT p300和乙酰化组蛋白H3和H4的募集。相反，在cFLIP启动子上，NF-κ B增加组蛋白去乙酰化酶1（HDAC 1），减少p300和组蛋白乙酰化，并减少NFAT（一种对cFLIP表达至关重要的转录因子）的募集。最后，我们发现了一个双相效应，当HDAC抑制剂（HDACi）被用来测试色素上皮衍生因子活性对组蛋白乙酰化的依赖性。随着浓度的增加，在低剂量下观察到的协同作用转变为拮抗作用。我们的研究定义了一个相互作用的转录网络血管生成的平衡和点HDACi作为工具来操纵血管生成开关。（血。2010; 116（3）：475-484）
Extracellular factors control the angiogenic switch in endothelial cells (ECs) via competing survival and apoptotic pathways. Previously, we showed that pro-angiogenic 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-kappa B (NF-kappa B) DNA binding, which is critical for antiangiogenesis, and that blocking the NF-kappa B pathway abol-ishes multiple antiangiogenic events in-vitro and in vivo. NF-kappa B induction by antiangiogenic molecules has a dual effect on transcription. NF-kappa B acts as an activator of proapoptotic FasL and as a repressor of prosurvival cFLIP. On the FasL promoter, NF-kappa B increases the recruitment of HAT p300 and acetylated histones H3 and H4. Conversely, on cFLIP promoter, NF-kappa B 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. (Blood. 2010; 116(3): 475-484)