Foxo1 deletion promotes the growth of new lymphatic valves
Foxo1 deletion promotes the growth of new lymphatic valves
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DOI：
10.1172/jci142341
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发表时间：
2021-07-15
影响因子：
15.9
通讯作者：
Yang, Ying
中科院分区：
文献类型：
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作者：
Scallan, Joshua P.;Knauer, Luz A.;Yang, Ying
患有先天性水肿的患者遭受组织肿胀，部分原因是调节淋巴瓣发育的基因突变。淋巴瓣小叶生长并在整个生命过程中响应于振荡剪切应力（OSS）而维持，其调节淋巴管内皮细胞（LEC）中的基因转录。在这里，我们确定了第一个转录因子，Foxo 1，通过抑制瓣膜形成基因的表达来抑制淋巴管瓣膜的形成。我们发现，胚胎和出生后在LEC中的Foxo 1的消融在出生后和成年小鼠的多个组织中诱导了额外的瓣膜形成。我们的定量分析显示，缺失后，与Foxo 1fl/fl对照组相比，Foxo 1 LEC-KO小鼠肠系膜中的瓣膜总数显著增加（P < 0.01）。此外，我们的实时定量PCR（RT-PCR）数据显示，许多瓣膜形成基因的FOXO 1敲低后显着（P < 0.01）上调。为了证实我们在体内的发现，救援实验表明，Foxc 2（+/-）小鼠，一种双股骨头水肿模型，淋巴管瓣膜减少了50%，其余的瓣膜表现出回漏。Foxo 1缺失后，瓣膜数量和功能均完全恢复至对照水平。这些发现确立了FOXO 1作为刺激新生淋巴瓣形成和挽救先天性水肿中有缺陷的瓣膜的临床相关靶点。
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.