MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation.
MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation.
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DOI：
10.1038/ncomms11268
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发表时间：
2016-04-12
影响因子：
16.6
通讯作者：
Chun HJ
中科院分区：
文献类型：
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作者：
Papangeli I;Kim J;Maier I;Park S;Lee A;Kang Y;Tanaka K;Khan OF;Ju H;Kojima Y;Red-Horse K;Anderson DG;Siekmann AF;Chun HJ
已知G蛋白偶联受体（GPCR）信号传导，包括涉及appln及其受体APLNR的信号传导，在血管发育中起重要作用。在这种情况下，这种配体-受体对如何调节下游信号级联仍然知之甚少。在这里，我们发现Apln、Aplnr或内皮特异性Aplnr缺失的小鼠会发生严重的视网膜血管缺陷，这至少部分是由于内皮细胞CXCR4表达的失调增加。内皮细胞的CXCR4受miR-139-5p的负调控，miR-139-5p的转录反过来由层流和APLN/APLNR信号传导诱导。体内miR-139-5p的抑制部分反映了APLN/APLNR缺乏症的视网膜血管缺陷。药理抑制CXCR4信号传导或增强miR-139-5p-CXCR4轴可改善APLN/APLNR缺陷状态的血管表型。总的来说，我们发现了一个重要的microrna介导的GPCR串扰，它在血管发育中起着关键作用。G蛋白偶联受体APLNR和CXCR4对血管发育至关重要。在这里，作者表明这两种信号通路相互交流，并且作为对血流的响应，APLNR信号通过miR-139-5p诱导CXCR4表达减少，从而限制了CXCR4在视网膜脉管系统中未流动暴露的尖端细胞中的表达。
G protein-coupled receptor (GPCR) signalling, including that involving apelin (APLN) and its receptor APLNR, is known to be important in vascular development. How this ligand–receptor pair regulates the downstream signalling cascades in this context remains poorly understood. Here, we show that mice with Apln, Aplnr or endothelial-specific Aplnr deletion develop profound retinal vascular defects, which are at least in part due to dysregulated increase in endothelial CXCR4 expression. Endothelial CXCR4 is negatively regulated by miR-139-5p, whose transcription is in turn induced by laminar flow and APLN/APLNR signalling. Inhibition of miR-139-5p in vivo partially phenocopies the retinal vascular defects of APLN/APLNR deficiency. Pharmacological inhibition of CXCR4 signalling or augmentation of the miR-139-5p-CXCR4 axis can ameliorate the vascular phenotype of APLN/APLNR deficient state. Overall, we identify an important microRNA-mediated GPCR crosstalk, which plays a key role in vascular development. G protein-coupled receptors APLNR and CXCR4 are crucial for vascular development. Here, the authors show that these two signaling pathways communicate and that in response to blood flow APLNR signaling induces a decrease in CXCR4 expression via miR-139-5p, thereby restricting CXCR4 expression to the non-flow exposed tip cells in the retinal vasculature.