Division of Experimental Oncology, Multidisciplinary Oncology Center, University Hospital of Lausanne, Switzerland.
Dev Cell. 2012 Feb 14;22(2):430-45. doi: 10.1016/j.devcel.2011.12.020. Epub 2012 Feb 2.
Lymphatic valves are essential for efficient lymphatic transport, but the mechanisms of early lymphatic-valve morphogenesis and the role of biomechanical forces are not well understood. We found that the transcription factors PROX1 and FOXC2, highly expressed from the onset of valve formation, mediate segregation of lymphatic-valve-forming cells and cell mechanosensory responses to shear stress in vitro. Mechanistically, PROX1, FOXC2, and flow coordinately control expression of the gap junction protein connexin37 and activation of calcineurin/NFAT signaling. Connexin37 and calcineurin are required for the assembly and delimitation of lymphatic valve territory during development and for its postnatal maintenance. We propose a model in which regionally increased levels/activation states of transcription factors cooperate with mechanotransduction to induce a discrete cell-signaling pattern and morphogenetic event, such as formation of lymphatic valves. Our results also provide molecular insights into the role of endothelial cell identity in the regulation of vascular mechanotransduction.
淋巴管瓣对于有效的淋巴转运至关重要，但早期淋巴管瓣形成的机制以及生物力学的作用尚不清楚。我们发现，转录因子 PROX1 和 FOXC2 从瓣膜形成开始就高度表达，介导淋巴管瓣形成细胞的隔离和细胞对体外切应力的机械感觉反应。从机制上讲，PROX1、FOXC2 和流动协调控制缝隙连接蛋白 connexin37 的表达和钙调神经磷酸酶/NFAT 信号的激活。在发育过程中，connexin37 和钙调神经磷酸酶对于淋巴管瓣区域的形成和限定以及其出生后的维持是必需的。我们提出了一个模型，即区域内转录因子水平/激活状态的增加与机械转导协同作用，诱导离散的细胞信号模式和形态发生事件，如淋巴管瓣的形成。我们的研究结果还为内皮细胞特性在血管机械转导调节中的作用提供了分子见解。
