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首页> 外文期刊>Molecular and Cellular Biology >Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function
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Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function

机译：内皮细胞丝裂原激活的蛋白激酶激酶激酶激酶4对于淋巴管的发育和功能至关重要。

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摘要

The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein Rasa1, a known regulator of lymphatic development and lymphatic endothelial cell fate, as a direct interacting partner for Map4k4. Map4k4 silencing in ECs enhanced basal Ras and extracellular signal-regulated kinase (Erk) activities, and primary ECs lacking Map4k4 displayed enhanced lymphatic EC marker expression. Taken together, these results reveal that EC Map4k4 is critical for lymphatic vascular development by regulating EC quiescence and lymphatic EC fate.
机译：淋巴管发育和功能的分子机制尚不清楚。最近的研究表明内皮细胞（EC）促分裂原活化蛋白激酶激酶激酶激酶激酶4（Map4k4）在发育性血管生成和动脉粥样硬化中的作用。在这里，我们显示，小鼠乳糜泻中EC Map4k4的组成性丧失会导致因乳糜胸而致死，这表明Map4k4是正常淋巴管功能所必需的。组成型缺乏EC Map4k4的小鼠表现出淋巴毛细血管扩张，淋巴阀不足和淋巴流动受损;此外，与对照组相比，源自这些动物的原代EC具有增强的增殖能力。酵母2杂交分析确定Ras GTPase激活蛋白Rasa1（一种已知的淋巴发育和淋巴管内皮细胞命运的调节剂）是Map4k4的直接相互作用伴侣。 EC4中的Map4k4沉默增强了基础Ras和细胞外信号调节激酶（Erk）的活性，而缺乏Map4k4的原发性ECs增强了淋巴EC标志物的表达。综上所述，这些结果表明，EC Map4k4通过调节EC的静止和淋巴管的EC命运对于淋巴管的发育至关重要。

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