Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function.
Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function.
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DOI：
10.1126/scisignal.2005413
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发表时间：
2014-10-14
影响因子：
7.3
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Liu X;Pasula S;Song H;Tessneer KL;Dong Y;Hahn S;Yago T;Brophy ML;Chang B;Cai X;Wu H;McManus J;Ichise H;Georgescu C;Wren JD;Griffin C;Xia L;Srinivasan RS;Chen H
淋巴瓣防止淋巴液回流，确保全身淋巴液正常引流。淋巴液在组织中局部积聚，称为淋巴水肿，在淋巴瓣畸形的个体中很常见。血管内皮生长因子受体3（VEGFR3）是淋巴管系统发育所必需的。在瓣膜形成前，集合淋巴干中 VEGFR3 的丰度较高，而在瓣膜形成后，除瓣膜区域外，VEGFR3 的丰度降低。我们发现，在肠系膜淋巴管中，epsin 1 和 2（参与内吞作用的泛素结合接头蛋白）的丰度在发育早期阶段较低。淋巴瓣形成后，稳定剪切流的启动与集合淋巴干中epsin 1和2丰度的增加有关，但与瓣膜区域无关。 Epsin 1 和 2 与 VEGFR3 结合并介导 VEGFR3 的内化和降解，导致 VEGFR3 信号传导终止。淋巴内皮细胞特异性缺乏epsin 1和2的小鼠具有扩张的毛细淋巴管、集合淋巴管中异常高的VEGFR3丰度、不成熟的淋巴瓣膜和有缺陷的淋巴引流。删除单个 Vegfr3 等位基因或药物抑制 VEGFR3 信号传导可恢复 epsin 缺陷小鼠的正常淋巴瓣发育和淋巴引流。我们的研究结果表明，epsins 在 VEGFR3 丰度的时间和空间调节以及淋巴瓣形成过程中收集淋巴干的信号传导中发挥着关键作用。
Lymphatic valves prevent the backflow of the lymph fluid and ensure proper lymphatic drainage throughout the body. Local accumulation of lymphatic fluid in tissues, a condition called lymphedema, is common in individuals with malformed lymphatic valves. The vascular endothelial growth factor receptor 3 (VEGFR3) is required for the development of lymphatic vascular system. The abundance of VEGFR3 in collecting lymphatic trunks is high before valve formation and, except at valve regions, decreases after valve formation. We found that in mesenteric lymphatics, the abundance of epsin 1 and 2, which are ubiquitin-binding adaptor proteins involved in endocytosis, was low at early stages of development. After lymphatic valve formation, the initiation of steady shear flow was associated with an increase in the abundance of epsin 1 and 2 in collecting lymphatic trunks, but not in valve regions. Epsin 1 and 2 bound to VEGFR3 and mediated the internalization and degradation of VEGFR3, resulting in termination of VEGFR3 signaling. Mice with lymphatic endothelial cell-specific deficiency of epsin 1 and 2 had dilated lymphatic capillaries, abnormally high VEGFR3 abundance in collecting lymphatics, immature lymphatic valves, and defective lymph drainage. Deletion of a single Vegfr3 allele or pharmacological suppression of VEGFR3 signaling restored normal lymphatic valve development and lymph drainage in epsin-deficient mice. Our findings establish a critical role for epsins in the temporal and spatial regulation of VEGFR3 abundance and signaling in collecting lymphatic trunks during lymphatic valve formation.
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影响因子：
11.8
作者：
Bazigou, Eleni;Xie, Sherry;Chen, Chun;Weston, Anne;Miura, Naoyuki;Sorokin, Lydia;Adams, Ralf;Muro, Andres F.;Sheppard, Dean;Makinen, Taija
通讯作者：
Makinen, Taija
影响因子：
20.3
作者：
Bertozzi, Cara C.;Schmaier, Alec A.;Kahn, Mark L.
通讯作者：
Kahn, Mark L.
DOI：
10.1073/pnas.0907008106
发表时间：
2009-08-18
影响因子：
11.1
作者：
Chen, Hong;Ko, Genevieve;Cremona, Ottavio
通讯作者：
Cremona, Ottavio
影响因子：
4.8
作者：
Jin, ZG;Wong, C;Berk, BC
通讯作者：
Berk, BC
影响因子：
56.9
作者：
Dumont, DJ;Jussila, L;Alitalo, K
通讯作者：
Alitalo, K