Synergistic Role of Endothelial ERG and FLI1 in Mediating Pulmonary Vascular Homeostasis
Synergistic Role of Endothelial ERG and FLI1 in Mediating Pulmonary Vascular Homeostasis
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DOI：
10.1165/rcmb.2016-0200oc
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发表时间：
2017-07-01
影响因子：
6.4
通讯作者：
Trojanowska, Maria
中科院分区：
文献类型：
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作者：
Looney, Agnieszka P.;Han, Rong;Trojanowska, Maria
内皮细胞（EC）激活是许多血管疾病的基础，包括肺动脉高压（PAH）。转录因子E-26（ETS）家族的几个成员是控制内皮稳态的基因网络的重要调节因子，并且它们的异常表达与病理性血管生成相关。本研究的目的是确定ETS家族成员Friend白血病整合1转录因子（FLI 1）及其最接近的同源物ETS相关基因（ERG）的缺陷是否与PAH相关。我们发现，内皮ERG显着降低肺动脉高压患者的肺样本，以及在慢性缺氧小鼠。功能研究表明，人肺EC中ERG或FLI 1的缺失导致炎症基因（包括IFN基因）表达增加，而调节内皮稳态和细胞-细胞粘附的基因下调。同时敲除ERG和FLI 1对这些基因的表达具有协同或累加效应，表明ERG和FLI 1共调节至少一个亚组的靶基因。在功能上，ERG和FLI 1的敲低诱导细胞单层通透性，其效力与血管内皮生长因子相似。值得注意的是，用Toll样受体3配体poly（I：C）刺激EC抑制ERG表达并诱导ERG从IFNB 1启动子解离，同时促进信号转导子和转录激活子1（STAT 1）募集。与体外观察到的炎症基因上调一致，Erg和Fli 1双杂合子小鼠显示肺中免疫细胞浸润和细胞因子表达增加。总之，ERG和FLI 1的缺失可能通过诱导炎症而导致血管性肺并发症的发病机制。
Endothelial cell (EC) activation underlies many vascular diseases, including pulmonary arterial hypertension (PAH). Several members of the E-twenty six (ETS) family of transcription factors are important regulators of the gene network governing endothelial homeostasis, and their aberrant expression is associated with pathological angiogenesis. The goal of this study was to determine whether deficiencies of the ETS family member, Friend leukemia integration 1 transcription factor (FLI1), and its closest homolog, ETS-related gene (ERG), are associated with PAH. We found that endothelial ERG was significantly reduced in the lung samples from patients with PAH, as well as in chronically hypoxic mice. Functional studies revealed that depletion of ERG or FLI1 in human pulmonary ECs led to increased expression of inflammatory genes, including IFN genes, whereas genes regulating endothelial homeostasis and cell-cell adhesion were down-regulated. Simultaneous knockdown of both ERG and FLI1 had synergistic or additive effects on the expression of these genes, suggesting that ERG and FLI1 coregulate at least a subset of their target genes. Functionally, knockdown of ERG and FLI1 induced cell monolayer permeability with a potency similar to that of vascular endothelial growth factor. Notably, stimulation of ECs with Toll-like receptor 3 ligand poly(I:C) suppressed ERG expression and induced ERG dissociation from the IFNB1 promoter, while promoting signal transducers and activators of transcription 1 (STAT1) recruitment. Consistent with the up-regulation of inflammatory genes seen in vitro, Erg and Fli1 double-heterozygote mice showed increased immune cell infiltration and expression of cytokines in the lung. In conclusion, loss of ERG and FLI1 might contribute to the pathogenesis of vascular lung complications through the induction of inflammation.