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首页> 外文期刊>The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation >Foxo1 deletion promotes the growth of new lymphatic valves
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Foxo1 deletion promotes the growth of new lymphatic valves

机译：Foxo1缺失促进新淋巴管的生长

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Patients with congenital lymphedema suffer from tissue swelling in part due to mutations in genes regulating lymphatic valve development. Lymphatic valve leaflets grow and are maintained throughout life in response to oscillatory shear stress (OSS), which regulates gene transcription in lymphatic endothelial cells (LECs). Here, we identified the first transcription factor, Foxo1, that repressed lymphatic valve formation by inhibiting the expression of valve-forming genes. We showed that both embryonic and postnatal ablation of Foxo1 in LECs induced additional valve formation in postnatal and adult mice in multiple tissues. Our quantitative analyses revealed that after deletion, the total number of valves in the mesentery was significantly (P < 0.01) increased in the Foxo1LEC-KO mice compared with Foxo1fl/fl controls. In addition, our quantitative real-time PCR (RT-PCR) data from cultured LECs showed that many valve-forming genes were significantly (P < 0.01) upregulated upon knockdown of FOXO1. To confirm our findings in vivo, rescue experiments showed that Foxc2(+/-) mice, a model of lymphedema-distichiasis, had 50 fewer lymphatic valves and that the remaining valves exhibited backleak. Both valve number and function were completely restored to control levels upon Foxo1 deletion. These findings established FOXO1 as a clinically relevant target to stimulate de novo lymphatic valve formation and rescue defective valves in congenital lymphedema.
机译：先天性淋巴水肿患者出现组织肿胀，部分原因是调节淋巴管发育的基因突变。淋巴瓣小叶在振荡剪切应力 （OSS） 的响应下生长并维持一生，OSS 调节淋巴内皮细胞 （LEC） 中的基因转录。在这里，我们鉴定了第一个转录因子Foxo1，它通过抑制瓣膜形成基因的表达来抑制淋巴管的形成。我们发现，LEC中Foxo1的胚胎和出生后消融都诱导了多个组织中出生后和成年小鼠的额外瓣膜形成。定量分析显示，与Foxo1fl/fl对照组相比，Foxo1LEC-KO小鼠的肠系膜瓣膜总数显著增加（P<0.01）。此外，来自培养的 LEC 的定量实时 PCR （RT-PCR） 数据显示，许多瓣膜形成基因在敲低 FOXO1 后显着上调 （P < 0.01）。为了证实我们在体内的发现，抢救实验表明，淋巴水肿-双裂症模型Foxc2（+/-）小鼠的淋巴瓣减少了50%，其余瓣膜表现出回漏。在Foxo1缺失后，瓣膜数量和功能都完全恢复到控制水平。这些发现将 FOXO1 确立为临床相关靶点，可刺激先天性淋巴水肿中新发淋巴管形成并挽救有缺陷的瓣膜。

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