Homeostatic maintenance and repair of lymphatic vessels are essential for health. We investigated the dynamics and the molecular mechanisms of lymphatic endothelial cell (LEC) renewal in adult mesenteric quiescent lymphatic vasculature using label-retention, lineage tracing, and cell ablation strategies. Unlike during development, adult LEC turnover and proliferation was confined to the valve regions of collecting vessels, with valve cells displaying the shortest lifespan. Proliferating valve sinus LECs were the main source for maintenance and repair of lymphatic valves. We identified mechanistic target of rapamycin complex 1 (mTORC1) as a mechanoresponsive pathway activated by fluid shear stress in LECs. Depending on the shear stress level, mTORC1 activity drives division of valve cells or dictates their mechanic resilience through increased protein synthesis. Overactivation of lymphatic mTORC1 in vivo promoted supernumerary valve formation. Our work provides insights into the molecular mechanisms of maintenance of healthy lymphatic vascular system.

中文翻译：

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机械敏感的 mTORC1 信号维持淋巴瓣膜

淋巴管的稳态维持和修复对于健康至关重要。我们使用标记保留、谱系追踪和细胞消融策略研究了成人肠系膜静止淋巴管系统中淋巴内皮细胞（LEC）更新的动力学和分子机制。与发育过程不同，成体 LEC 的周转和增殖仅限于集合管的瓣膜区域，瓣膜细胞的寿命最短。增殖的瓣膜窦LECs是维持和修复淋巴瓣膜的主要来源。我们确定雷帕霉素复合物 1 (mTORC1) 的机械靶点是 LEC 中由流体剪切应力激活的机械响应途径。根据剪切应力水平，mTORC1 活性驱动瓣膜细胞分裂或通过增加蛋白质合成来决定其机械弹性。体内淋巴管 mTORC1 的过度激活促进了多余瓣膜的形成。我们的工作提供了对维持健康淋巴血管系统的分子机制的见解。