[HTML][HTML] VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis

L Zhang, F Zhou, W Han, B Shen, J Luo, M Shibuya… - Cell research, 2010 - nature.com
L Zhang, F Zhou, W Han, B Shen, J Luo, M Shibuya, Y He
Cell research, 2010nature.com
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 …
Abstract
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.
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