摘要
尽管 VEGFR-3 缺乏破坏血脉管的开发在早 embryogenesis 期间,内在的机制不是清楚的。在 angiogenesis 和 lymphangiogenesis 描绘它的函数,我们在这研究雇用了二个遗传上修改的鼠标模特儿,与一个 inactivation 点变化(Vegfr3TKmut ) 为 ligand 有约束力的域(Vegfr3 螖 L BD ) 或酷氨酸 kinase 域指向编码区域。我们证明淋巴的生长在 Vegfr3 螖 L BD/螖 L BD 和 Vegfr3TKmut/TKmut 老鼠被破坏,但是血容器在胚胎和蛋黄囊通常发展了。有趣地在 Vegfr3 螖 L BD/螖 L BD 然而并非 Vegfr3TKmut/TKmut 老鼠,淋巴囊是在场的,但是有发芽的 lymphangiogenic 的缺乏。我们进一步证明 VEGFR-3 的野类型、变异的形式能与 VEGFR-2 形成 heterodimers,并且减少在 endothelial 房间的 phospho-VEGFR-2 和下游的 phospho-Erk1/2 的水平当他们与 VEGF 被对待时 -- 一。这些调查结果显示发信号由它的血缘的 ligands (VEGF-C/-D ) 经由 VEGFR-3 激活调停了没为 angiogenesis 被要求,并且那 VEGFR-3 可以由 modulating VEGFR-2-mediated 信号在这个过程起一个作用。
Although VEGFR-3 deficiency disrupts blood vascular development during early embryogenesis, the underlying mechanism was not clear. To characterize its function in angiogenesis and lymphangiogenesis, we employed two genetically modified mouse models in this study, targeting the coding region for the ligand-binding domain (Vegfr△LBD) or the tyrosine kinase domain with an inactivation point mutation (Vegfr3^TKmat). We show that lymphatic growth was disrupted in Vegfr3△LBD/△LBD and Vegfr3^TKmut3^TKmat mice, but blood vessels developed normally in both embryo and yolk sac. Interestingly, in Vegfr3△LBD/△LBD but not Vegfr3^TKmut3^TKmat mice, lymph sac was present but there was lack of iym- phangiogenic sprouting. We further demonstrate that both the wild-type and mutant forms of VEGFR-3 could form heterodimers with VEGFR-2, and decreased the level of phospho-VEGFR-2 and the downstream phospho-Erk1/2 in endothelial cells when they were treated with VEGF-A. These findings indicate that signaling mediated via VEGFR-3 activation by its cognate ligands (VEGF-C/-D) is not required for angiogenesis, and that VEGFR-3 may play a role in this process by modulating VEGFR-2-mediated signals.
基金
Acknowledgments We thank Dr Lena Claesson-Welsh (Uppsala University), and PIs of Model Animal Research Center (MARC, Nanjing University) for the helpful discussion about the work, and Yanlan Cao, Wenting Shi and all the staff in the MARC Animal facility of Nanjing University for excellent technical assistance. This work wasfinancially supported by grants from the National Natural Science Foundation of China (30771069, 30671038, and 30930028), the Ministry of Science and Technology of China (2006CB943500), and the Ministry of Education of China (NCET: Program for New Century Excellent Talents in University).