VE-Cadherin Is Required for Lymphatic Valve Formation and Maintenance
VE-Cadherin Is Required for Lymphatic Valve Formation and Maintenance
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DOI：
10.1016/j.celrep.2019.07.072
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发表时间：
2019-08-27
期刊：
影响因子：
8.8
通讯作者：
Scallan, Joshua P.
中科院分区：
文献类型：
--
作者：
Yang, Ying;Cha, Boksik;Scallan, Joshua P.
淋巴管系统需要管腔内的瓣膜来维持向前的淋巴流动。淋巴瓣膜的形成和维持在整个生命周期中都由振荡的流体流动维持，然而淋巴管内皮细胞如何对流体剪切力做出反应的最早步骤仍不清楚。在这里，我们证明了黏附连接蛋白VE-钙粘附素是瓣膜特异性转录因子上调所必需的。体内VE-钙粘附素的有条件缺失阻止了胚胎中瓣膜的形成，并导致了多种组织中几乎所有淋巴瓣的出生后退化。由于已知VE-钙粘蛋白通过β-连环蛋白和VEGFR/AKT途径发出信号，因此对每种途径都进行了探讨。表达结构性活性的β-连环蛋白突变体或在体内直接药物激活AKT可显著挽救VE-钙粘附素缺乏的淋巴管中的瓣膜退变。总而言之，淋巴瓣的形成和维持需要依赖VE钙粘附素的信号，治疗需要增加下游通路的潜力，以治疗患者的淋巴水肿。
The lymphatic vasculature requires intraluminal valves to maintain forward lymph flow. Lymphatic valves form and are constantly maintained by oscillatory fluid flow throughout life, yet the earliest steps of how lymphatic endothelial cells are able to respond to fluid shear stress remain unknown. Here, we show that the adherens junction protein VE-cadherin is required for the upregulation of valve-specific transcription factors. Conditional deletion of VE-cadherin in vivo prevented valve formation in the embryo and caused postnatal regression of nearly all lymphatic valves in multiple tissues. Since VE-cadherin is known to signal through beta-catenin and the VEGFR/AKT pathway, each pathway was probed. Expression of a constitutively active beta-catenin mutant or direct pharmacologic activation of AKT in vivo significantly rescued valve regression in the VE-cadherindeficient lymphatic vessels. In conclusion, VE-cadherin-dependent signaling is required for lymphatic valve formation and maintenance and therapies to augment downstream pathways hold potential to treat lymphedema in patients.