Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves.
Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves.
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DOI：
10.1101/gad.282400.116
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发表时间：
2016-06-15
影响因子：
10.5
通讯作者：
Srinivasan RS
中科院分区：
文献类型：
--
作者：
Cha B;Geng X;Mahamud MR;Fu J;Mukherjee A;Kim Y;Jho EH;Kim TH;Kahn ML;Xia L;Dixon JB;Chen H;Srinivasan RS
在这项研究中，Cha等人表明Wnt/β-catenin信号通路是液体流动和淋巴管形态发生之间的联系。他们通过证明机械刺激是通过激活Wnt/β-连环蛋白信号传导的淋巴管发育的关键调节剂，为研究哺乳动物淋巴管系统提供了分子和结构框架。淋巴管系统通过使组织间液返回血液循环来调节体液平衡。淋巴管内皮细胞（LEC）是整个淋巴管系统的基石。LEC起源于主要来自胚胎静脉的同质细胞群，并经历逐步的形态发生以成为毛细淋巴管、集合管或瓣膜。淋巴管系统形态发生的分子机制仍有待充分理解。在这里，我们表明，经典的Wnt/β-catenin信号是必要的淋巴管形态发生。小鼠中β-连环蛋白的淋巴血管特异性消融可防止淋巴和淋巴静脉瓣膜的形成。此外，这些小鼠的淋巴管图案是有缺陷的，具有壁细胞的异常募集。我们发现，振荡剪切应力（OSS），促进淋巴管成熟，触发Wnt/β-catenin信号在LEC。反过来，Wnt/β-连环蛋白信号传导控制几种分子的表达，包括水肿相关转录因子FOXC 2。重要的是，FOXC 2完全挽救了缺乏β-连环蛋白的小鼠的淋巴管图案缺陷。因此，我们的工作揭示了机械刺激是通过激活Wnt/β-catenin信号传导，进而激活FOXC 2的淋巴管发育的关键调节剂。
In this study, Cha et al. show that the Wnt/β-catenin signaling pathway is the link between fluid flow and lymphatic vascular morphogenesis. They provide a molecular and structural framework to study mammalian lymphatic vasculature by demonstrating that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/β-catenin signaling. Lymphatic vasculature regulates fluid homeostasis by returning interstitial fluid to blood circulation. Lymphatic endothelial cells (LECs) are the building blocks of the entire lymphatic vasculature. LECs originate as a homogeneous population of cells predominantly from the embryonic veins and undergo stepwise morphogenesis to become the lymphatic capillaries, collecting vessels or valves. The molecular mechanisms underlying the morphogenesis of the lymphatic vasculature remain to be fully understood. Here we show that canonical Wnt/β-catenin signaling is necessary for lymphatic vascular morphogenesis. Lymphatic vascular-specific ablation of β-catenin in mice prevents the formation of lymphatic and lymphovenous valves. Additionally, lymphatic vessel patterning is defective in these mice, with abnormal recruitment of mural cells. We found that oscillatory shear stress (OSS), which promotes lymphatic vessel maturation, triggers Wnt/β-catenin signaling in LECs. In turn, Wnt/β-catenin signaling controls the expression of several molecules, including the lymphedema-associated transcription factor FOXC2. Importantly, FOXC2 completely rescues the lymphatic vessel patterning defects in mice lacking β-catenin. Thus, our work reveals that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/β-catenin signaling and, in turn, FOXC2.