FOXO1 represses lymphatic valve formation and maintenance via PRDM1
FOXO1 represses lymphatic valve formation and maintenance via PRDM1
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DOI：
10.1016/j.celrep.2021.110048
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发表时间：
2021-11-30
期刊：
影响因子：
8.8
通讯作者：
Furuyama, Tatsuo
中科院分区：
文献类型：
--
作者：
Niimi, Kenta;Nakae, Jun;Furuyama, Tatsuo
腔内淋巴阀（lv）有助于防止淋巴回流和维持循环稳态。一些报道研究了促进LV形成的分子机制；然而，它们被抑制的方式并不完全清楚。我们发现叉头转录因子FOXO1是淋巴内皮细胞LV形成和维持的抑制因子。双向流动的振荡剪切应力通过Akt磷酸化使FOXO1失活，导致转录抑制因子PRDM1下调介导的一组lv特异性基因上调。内皮特异性Foxo1缺失小鼠的LVs增加，Foxo1过表达小鼠的LVs减少。PRDM1基因的减少通过Foxo1过表达挽救了LV的下降。综上所述，fox01通过阻止过多LV的形成，在淋巴流动稳态中起关键作用。该基因可能是淋巴循环异常的治疗靶点。
Intraluminal lymphatic valves (LVs) contribute to the prevention of lymph backflow and maintain circulatory homeostasis. Several reports have investigated the molecular mechanisms which promote LV formation; however, the way in which they are suppressed is not completely clear. We show that the forkhead transcription factor FOXO1 is a suppressor of LV formation and maintenance in lymphatic endothelial cells. Oscillatory shear stress by bidirectional flow inactivates FOXO1 via Akt phosphorylation, resulting in the upregulation of a subset of LV-specific genes mediated by downregulation of a transcriptional repressor, PRDM1. Mice with an endothelial-specific Foxo1 deletion have an increase in LVs, and overexpression of Foxo1 in mice produces a decrease in LVs. Genetic reduction of PRDM1 rescues the decrease in LV by Foxo1 overexpression. In conclusion, FOXO1 plays a critical role in lymph flow homeostasis by preventing excess LV formation. This gene might be a therapeutic target for lymphatic circulatory abnormalities.