Journal
CELL RESEARCH
Volume 20, Issue 12, Pages 1319-1331Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2010.116
Keywords
VEGFR-3; ligand-binding domain; tyrosine kinase; angiogenesis; lymphangiogenesis
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Funding
- National Natural Science Foundation of China [30771069, 30671038, 30930028]
- Ministry of Science and Technology of China [2006CB943500]
- Ministry of Education of China
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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(Delta LBD)) or the tyrosine kinase domain with an inactivation point mutation (Vegfr3(TKmut)). We show that lymphatic growth was disrupted in Vegfr3(Delta LBD/Delta LBD) and Vegfr3(TKmut/TKmut) mice, but blood vessels developed normally in both embryo and yolk sac. Interestingly, in Vegfr3(Delta LBD/Delta LBD) 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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