Liu Xiaolei, Pasula Satish, Song Hoogeun, Tessneer Kandice L, Dong Yunzhou, Hahn Scott, Yago Tadayuki, Brophy Megan L, Chang Baojun, Cai Xiaofeng, Wu Hao, McManus John, Ichise Hirotake, Georgescu Constantin, Wren Jonathan D, Griffin Courtney, Xia Lijun, Srinivasan R Sathish, Chen Hong
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma, OK 73104, USA.
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA.
Sci Signal. 2014 Oct 14;7(347):ra97. doi: 10.1126/scisignal.2005413.
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.
淋巴管瓣膜可防止淋巴液逆流，并确保全身淋巴液的正常引流。组织中淋巴液的局部积聚，即所谓的淋巴水肿，在淋巴管瓣膜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。在瓣膜形成之前，集合淋巴管中VEGFR3的丰度很高，而在瓣膜形成后，除了瓣膜区域外，其丰度会降低。我们发现，在肠系膜淋巴管中，参与内吞作用的泛素结合衔接蛋白epsin 1和2在发育早期的丰度较低。在淋巴管瓣膜形成后，稳定剪切流的启动与集合淋巴管中epsin 1和2丰度的增加有关，但瓣膜区域除外。Epsin 1和2与VEGFR3结合，介导VEGFR3的内化和降解，从而导致VEGFR3信号传导终止。Epsin 1和2在淋巴管内皮细胞中特异性缺失的小鼠出现淋巴管扩张、集合淋巴管中VEGFR3丰度异常高、淋巴管瓣膜不成熟以及淋巴引流缺陷。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管瓣膜发育和淋巴引流。我们的研究结果确定了epsins在淋巴管瓣膜形成过程中对集合淋巴管中VEGFR3丰度和信号传导的时空调节中的关键作用。
