The pro-inflammatory signalling regulator Stat4 promotes vasculogenesis of great vessels derived from endothelial precursors.
The pro-inflammatory signalling regulator Stat4 promotes vasculogenesis of great vessels derived from endothelial precursors.
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促炎信号调节因子 Stat4 促进源自内皮前体的大血管的血管生成
DOI：
10.1038/ncomms14640
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发表时间：
2017-03-03
影响因子：
16.6
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Meng ZZ;Liu W;Xia Y;Yin HM;Zhang CY;Su D;Yan LF;Gu AH;Zhou Y
大血管的血管源性缺陷是先天性心血管疾病的主要原因。然而，在GV血管发生的内皮前体的遗传调节因子仍然在很大程度上未知。在这里，我们表明，Stat 4，一个转录因子已知的促炎信号的调节作用，促进斑马鱼GV血管发生。我们发现stat 4转录本在咽部高度富集在nkx2.5+内皮前体细胞中，并证明stat 4基因消融通过抑制PAAs 3-6成血管细胞的发育导致咽弓动脉（PAAs）狭窄。我们进一步表明，stat 4是nkx2.5的下游靶点，它自主促进中胚层内皮前体细胞的增殖。stat 4通过抑制hdac 3的表达和抵消stat 1a的作用来调节新生的PAA成血管细胞。总之，我们的研究确立了Stat 4在斑马鱼大血管发育中的作用，并表明Stat 4可作为GV缺陷的治疗靶点。
Vasculogenic defects of great vessels (GVs) are a major cause of congenital cardiovascular diseases. However, genetic regulators of endothelial precursors in GV vasculogenesis remain largely unknown. Here we show that Stat4, a transcription factor known for its regulatory role of pro-inflammatory signalling, promotes GV vasculogenesis in zebrafish. We findstat4transcripts highly enriched innkx2.5+endothelial precursors in the pharynx and demonstrate that genetic ablation ofstat4causes stenosis of pharyngeal arch arteries (PAAs) by suppressing PAAs 3–6 angioblast development. We further show thatstat4is a downstream target ofnkx2.5and that it autonomously promotes proliferation of endothelial precursors of the mesoderm. Mechanistically,stat4regulates the emerging PAA angioblasts by inhibiting the expression ofhdac3and counteracting the effect ofstat1a. Altogether, our study establishes a role for Stat4 in zebrafish great vessel development, and suggests that Stat4 may serve as a therapeutic target for GV defects.