血管内皮生长因子受体-3配体结合域介导的信号在淋巴管新生和稳态维持中的作用

Objective: While vascular endothelial growth factor receptor-3 (VEGFR3) is known to play a critical role in lymphangiogenesis, its ligand-binding domain (LBD)-mediated signaling in lymphangiogenesis and homeostasis, particularly in different tissues, remain to be fully elucidated. Methods: We employed a genetically modified mouse model targeting the LBD of VEGFR3in this study. The induced gene deletion was performed at different developmental stages, including neonatal, juvenile and adult stages. Tissues including skin, trachea, intestine, and diaphragm from the mutant and control mice were collected for the analysis of lymphatic vessels. Results: Immunofluorescence staining revealed that the induced deletion of the VEGFR3LBD at the neonatal stage (P1-4) suppressed lymphangiogenesis in several tissues examined. There was a significant decrease of lymphatic vessel density in the abdominal as well as the tail skin, and also in the trachea mucosal layer of mutant mice compared with the control mice. Lack of lacteals in the intestinal villi and a marked decrease of lymphatics in the inner wall of colons were also observed in the Vegfr3lbd mutant mice. Consistently, lymphangiogenic sprouts were dramatically suppressed in the Vegfr3lbd mutant mice. Furthermore, we also observed some dilated lymphatic vessels in the dorsal skin and trachea of the heterozygous mice (Vegfr3lbd+/-, at P1), suggesting a dominant-negative effect of VEGFR3LBD. Induced deletion of the VEGFR3LBD at the juvenile stage (P16-21) led to a decrease of lymphatic vessel density in ear skin, while there was no obvious abnormality with lymphatic vessel formation detected in the diaphragm, trachea, and intestinal villi. Furthermore, the induced deletion of the VEGFR3LBD did not produce obvious lymphatic phenotype in several tissue examined at the adult stage (2 month-old). However, there was some dilated lymphatic vessels detected in the diaphragm and skin of the Vegfr3lbd mutant mice. Conclusion: In summary, findings from this study indicate that the VEGFR3LBD-mediated signaling is essential for lymphangiogenesis at the neonatal stage, but is less required for the lymphatic vessel growth and maintenance from the juvenile stage onwards. It is worth noting that the dilation of lymphatic vessels observed in some Vegfr3lbd mutant mice at the adult stage may be related to the developmental lymphatic defects resulting from the dominant-negative effect of VEGFR3LBD.