Bazigou Eleni, Xie Sherry, Chen Chun, Weston Anne, Miura Naoyuki, Sorokin Lydia, Adams Ralf, Muro Andrés F, Sheppard Dean, Makinen Taija
Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Dev Cell. 2009 Aug;17(2):175-86. doi: 10.1016/j.devcel.2009.06.017.
Dysfunction of lymphatic valves underlies human lymphedema, yet the process of valve morphogenesis is poorly understood. Here, we show that during embryogenesis, lymphatic valve leaflet formation is initiated by upregulation of integrin-alpha9 expression and deposition of its ligand fibronectin-EIIIA (FN-EIIIA) in the extracellular matrix. Endothelial cell-specific deletion of Itga9 (encoding integrin-alpha9) in mouse embryos results in the development of rudimentary valve leaflets characterized by disorganized FN matrix, short cusps, and retrograde lymphatic flow. Similar morphological and functional defects are observed in mice lacking the EIIIA domain of FN. Mechanistically, we demonstrate that in primary human lymphatic endothelial cells, the integrin-alpha9-EIIIA interaction directly regulates FN fibril assembly, which is essential for the formation of the extracellular matrix core of valve leaflets. Our findings reveal an important role for integrin-alpha9 signaling during lymphatic valve morphogenesis and implicate it as a candidate gene for primary lymphedema caused by valve defects.
淋巴管瓣膜功能障碍是人类淋巴水肿的基础，但瓣膜形态发生过程却知之甚少。在此，我们表明，在胚胎发育过程中，淋巴管瓣膜小叶的形成是由整合素α9表达上调及其配体纤连蛋白-EIIIA（FN-EIIIA）在细胞外基质中的沉积所启动的。小鼠胚胎中内皮细胞特异性缺失Itga9（编码整合素α9）会导致发育出基本的瓣膜小叶，其特征为FN基质紊乱、尖瓣短小以及淋巴液逆流。在缺乏FN的EIIIA结构域的小鼠中也观察到了类似的形态和功能缺陷。从机制上来说，我们证明，在原代人淋巴管内皮细胞中，整合素α9-EIIIA相互作用直接调节FN纤维组装，这对于瓣膜小叶细胞外基质核心的形成至关重要。我们的研究结果揭示了整合素α9信号在淋巴管瓣膜形态发生过程中的重要作用，并表明它是由瓣膜缺陷引起的原发性淋巴水肿的候选基因。
