FOSL1 Controls the Assembly of Endothelial Cells into Capillary Tubes by Direct Repression of αv and β3 Integrin Transcription
FOSL1 Controls the Assembly of Endothelial Cells into Capillary Tubes by Direct Repression of αv and β3 Integrin Transcription
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DOI：
10.1128/mcb.01054-12
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发表时间：
2013-03-01
影响因子：
5.3
通讯作者：
Oliviero, Salvatore
中科院分区：
文献类型：
--
作者：
Evellin, Sandrine;Galvagni, Federico;Oliviero, Salvatore
为了形成三维毛细血管，内皮细胞必须与细胞外基质建立联系，细胞外基质为其增殖、迁移和分化提供信号。转录因子Fosl1在血管生成和血管发生过程中起关键作用，因为Fosl1基因敲除的胚胎会因胚外组织中的血管缺陷而死亡。在此，我们表明Fosl1（-/-）胚胎干细胞可分化为内皮细胞，但无法正确组装成原始毛细血管以及形成管状结构。FOSL1沉默影响体外血管生成，增加细胞黏附，并降低原代人内皮细胞（HUVEC）的细胞迁移能力。我们进一步表明FOSL1是αv和β3整合素表达的抑制因子，αvβ3的下调可挽救FOSL1沉默的HUVEC中的血管生成表型，而单独的αvβ3异位表达可重现FOSL1敲低所诱导的表型改变。FOSL1通过转录因子SP1与JunD一起结合到αv和β3整合素基因的近端启动子上，从而抑制这两个基因的转录。这些数据表明，内皮细胞上FOSL1依赖的αvβ3表达的负调控对于内皮组装成血管结构是必需的。
To form three-dimensional capillary tubes, endothelial cells must establish contacts with the extracellular matrix that provides signals for their proliferation, migration, and differentiation. The transcription factor Fosl1 plays a key role in the vasculogenic and angiogenic processes as Fosl1 knockout embryos die with vascular defects in extraembryonic tissues. Here, we show that Fosl1(-/-) embryonic stem cells differentiate into endothelial cells but fail to correctly assemble into primitive capillaries and to form tube-like structures. FOSL1 silencing affects in vitro angiogenesis, increases cell adhesion, and decreases cell mobility of primary human endothelial cells (HUVEC). We further show that FOSL1 is a repressor of alpha v and beta 3 integrin expression and that the down-modulation of alpha v beta 3 rescues the angiogenic phenotype in FOSL1-silenced HUVEC, while the ectopic expression of alpha v beta 3 alone reproduces the phenotypic alterations induced by FOSL1 knockdown. FOSL1 represses the transcription of both alpha v and beta 3 integrin genes by binding together with JunD to their proximal promoter via the transcription factor SP1. These data suggest that FOSL1-dependent negative regulation of alpha v beta 3 expression on endothelial cells is required for endothelial assembly into vessel structures.