FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature
FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature
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DOI：
10.1172/jci80454
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发表时间：
2015-10-01
影响因子：
15.9
通讯作者：
Petrova, Tatiana V.
中科院分区：
文献类型：
--
作者：
Sabine, Amelie;Bovay, Esther;Petrova, Tatiana V.
生物力学力，如流体剪切应力，支配内皮细胞生物学的多个方面。在血管中，扰动的流动与血管疾病（例如动脉粥样硬化）相关，并且促进内皮细胞增殖和凋亡。在这里，我们确定了一个重要的作用，在淋巴管中，它与转录因子FOXC 2合作，以确保淋巴管系统的终身稳定性的干扰流。在培养的淋巴管内皮细胞，FOXC 2失活赋予异常的剪切应力传感，促进连接解体和进入细胞周期。FOXC 2依赖性静止的丧失由Hippo途径转录辅激活因子TAZ介导，并最终导致细胞死亡。在小鼠模型中，淋巴管系统内Foxc 2的诱导性缺失导致细胞-细胞连接缺陷、瓣膜退化和局灶性血管腔塌陷，这引发了全身淋巴管功能障碍和致死性。总之，我们的工作描述了FOXC 2和振荡剪切应力通过细胞间连接和细胞骨架稳定维持淋巴管内皮细胞静止的基本机制，并提供了生物力学力和内皮细胞身份之间的重要联系，这是出生后血管稳态所必需的。由于FOXC 2在双股骨头水肿综合征中发生突变，我们的数据也强调了受损的机械传导在这种遗传性人类疾病的病理学中的作用。
Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.