Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice
Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice
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DOI：
10.1172/jci58050
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发表时间：
2011-08-01
影响因子：
15.9
通讯作者：
Makinen, Taija
中科院分区：
文献类型：
--
作者：
Bazigou, Eleni;Lyons, Oliver T. A.;Makinen, Taija
慢性静脉疾病和静脉高压是瓣膜关闭不全的常见后果，但调节静脉瓣形成和维持的分子机制尚未研究。在这里，我们提供了我们认为是静脉瓣形态发生的第一个描述，并确定了该过程所需的信号通路。研究发现，瓣膜发育的初始阶段涉及静脉内皮细胞诱导肝配蛋白-B2（动脉身份的关键标志物）。有趣的是，发育中和成熟的静脉瓣膜还表达一系列蛋白质，包括 Prox1 相关的 Prox1、Vegfr3 和整合素-α 9，这些蛋白质先前被认为是淋巴管生成的特异性和关键调节因子。使用整体和静脉瓣膜选择性敲除小鼠，我们进一步证明了肝配蛋白-B2 和整合素-α 9 信号传导对静脉瓣膜发育和维持的需求。因此，我们的研究结果确定了静脉瓣膜发育和维护的分子调节因子，并强调了常见形态发生过程和信号通路在控制静脉和淋巴管瓣膜形成中的参与。出乎意料的是，我们发现静脉瓣膜内皮细胞在分子水平上与淋巴（瓣膜）内皮细胞非常相似，这表明终末分化的内皮细胞具有不同表型特征的能力的可塑性。
Chronic venous disease and venous hypertension are common consequences of valve insufficiency, yet the molecular mechanisms regulating the formation and maintenance of venous valves have not been studied. Here, we provide what we believe to be the first description of venous valve morphogenesis and identify signaling pathways required for the process. The initial stages of valve development were found to involve induction of ephrin-B2, a key marker of arterial identity, by venous endothelial cells. Intriguingly, developing and mature venous valves also expressed a repertoire of proteins, including prospero-related homeobox 1 (Prox1), Vegfr3, and integrin-alpha 9, previously characterized as specific and critical regulators of lymphangiogenesis. Using global and venous valve-selective knockout mice, we further demonstrate the requirement of ephrin-B2 and integrin-alpha 9 signaling for the development and maintenance of venous valves. Our findings therefore identified molecular regulators of venous valve development and maintenance and highlighted the involvement of common morphogenetic processes and signaling pathways in controlling valve formation in veins and lymphatic vessels. Unexpectedly, we found that venous valve endothelial cells closely resemble lymphatic (valve) endothelia at the molecular level, suggesting plasticity in the ability of a terminally differentiated endothelial cell to take on a different phenotypic identity.