Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model.
Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model.
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DOI：
10.3389/fcell.2022.1024628
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发表时间：
2022
影响因子：
5.5
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中科院分区：
文献类型：
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许多调节淋巴瓣发育的基因突变与先天性水肿有关。来自淋巴的振荡剪切应力（OSS）为瓣膜细胞的生长和维持提供了持续的信号。淋巴管内皮细胞（LECs）中瓣膜形成基因的表达被OSS上调。转录因子FOXO 1通过抑制这些基因的表达来抑制淋巴管瓣的形成，这使得FOXO 1成为治疗水肿的潜在靶点。在这里，我们测试了FOXO 1抑制剂AS 1842856诱导新淋巴阀形成的能力。我们的定量RT-PCR和Western blot数据显示，用AS 1842856处理培养的人LEC 48 h显著增加了瓣膜形成基因的表达水平。为研究AS 1842856的体内功能，对Foxc 2 +/−小鼠（双列吸虫病小鼠模型）注射AS 1842856 2周。AS处理的Foxc 2 +/−小鼠的瓣膜数量显著高于溶剂处理的Foxc 2 +/−小鼠。此外，由于β-catenin在淋巴瓣形成过程中上调Foxc 2和Prox 1的表达，并且AS 1842856处理增加了体内培养的人LEC和小鼠肠系膜LEC中活性β-catenin的水平，因此我们使用具有组成性活性β-catenin的小鼠模型来挽救Foxc 2 +/−小鼠的淋巴瓣损失。Foxc 2 +/−小鼠的淋巴管瓣膜比对照组少50%，而补救实验表明，在细胞核β-连环蛋白激活后，瓣膜数量完全恢复到对照组水平。这些发现表明，FOXO 1的药理学抑制可以探索作为一种可行的策略，以解决先天性水肿的瓣膜缺陷。
Mutations in many genes that regulate lymphatic valve development are associated with congenital lymphedema. Oscillatory shear stress (OSS) from lymph provides constant signals for the growth and maintenance of valve cells throughout life. The expression of valve-forming genes in lymphatic endothelial cells (LECs) is upregulated by OSS. The transcription factor FOXO1 represses lymphatic valve formation by inhibiting the expression of these genes, which makes FOXO1 a potential target for treating lymphedema. Here, we tested the ability of a FOXO1 inhibitor, AS1842856, to induce the formation of new lymphatic valves. Our quantitative RT-PCR and Western blot data showed that treatment of cultured human LECs with AS1842856 for 48 h significantly increased the expression levels of valve-forming genes. To investigate the function of AS1842856 in vivo, Foxc2 +/− mice, the mouse model for lymphedema-distichiasis, were injected with AS1842856 for 2 weeks. The valve number in AS-treated Foxc2+/− mice was significantly higher than that of the vehicle-treated Foxc2+/− mice. Furthermore, since β-catenin upregulates the expression of Foxc2 and Prox1 during lymphatic valve formation, and AS1842856 treatment increased the level of active β-catenin in both cultured human LECs and in mouse mesenteric LECs in vivo, we used the mouse model with constitutive active β-catenin to rescue loss of lymphatic valves in Foxc2 +/− mice. Foxc2 +/− mice have 50% fewer lymphatic valves than control, and rescue experiments showed that the valve number was completely restored to the control level upon nuclear β-catenin activation. These findings indicate that pharmacological inhibition of FOXO1 can be explored as a viable strategy to resolve valve defects in congenital lymphedema.
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影响因子：
11.8
作者：
Bazigou, Eleni;Xie, Sherry;Chen, Chun;Weston, Anne;Miura, Naoyuki;Sorokin, Lydia;Adams, Ralf;Muro, Andres F.;Sheppard, Dean;Makinen, Taija
通讯作者：
Makinen, Taija
影响因子：
20.3
作者：
Kazenwadel, Jan;Secker, Genevieve A.;Harvey, Natasha L.
通讯作者：
Harvey, Natasha L.
影响因子：
7.3
作者：
Wang, Di;Wang, Yanqing;Tie, Lu
通讯作者：
Tie, Lu
影响因子：
2.7
作者：
Geng, Xin;Cha, Boksik;Srinivasan, R. Sathish
通讯作者：
Srinivasan, R. Sathish
影响因子：
3.5
作者：
Kriederman, BM;Myloyde, TL;Glover, TW
通讯作者：
Glover, TW