VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis.
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 (Vegfr3(ΔLBD)) or the tyrosine kinase domain with an inactivation point mutation (Vegfr3(TKmut)). We show that lymphatic growth was disrupted in Vegfr3(ΔLBD/ΔLBD) and Vegfr3(TKmut/TKmut) mice, but blood vessels developed normally in both embryo and yolk sac. Interestingly, in Vegfr3(ΔLBD/ΔLBD) but not Vegfr3(TKmut/TKmut) mice, lymph sac was present but there was lack of lymphangiogenic 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.
Zhang
Luqing
L
Laboratory of Vascular and Cancer Biology, MOE Key Laboratory for Model Animal and Disease Study, Model Animal Research Institute, Nanjing University, 12 Xue Fu Road, Nanjing 210061, China.
Zhou
Fei
F
Han
Wencan
W
Shen
Bin
B
Luo
Jincai
J
Shibuya
Masabumi
M
He
Yulong
Y
D000818:Animals; D019281:Dimerization; D004622:Embryo, Mammalian / Q000098:blood supply; D008024:Ligands; D042583:Lymphangiogenesis; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D023421:Models, Animal; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015017:Yolk Sac / Q000098:blood supply / Q000254:growth & development
D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3