期刊
NATURE CELL BIOLOGY
卷 13, 期 10, 页码 1202-1213出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2331
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资金
- Academy of Finland
- Association for International Cancer Research
- Finnish Cancer Organizations
- Helsinki University
- Sigrid Juselius Foundation
- Louis-Jeantet Foundation
- European Research Council [ERC-2010-AdG-268804-TX-FACTORS]
- Emil Aaltonen Foundation
- K. Albin Johansson Foundation
- Finnish Medical Foundation
- Maud Kuistila Foundation
- Orion-Farmos Research Foundation
- Paulo Foundation
- Ida Montin Foundation
- Cancer Research UK
- Lister Institute of Preventive Medicine
- European Molecular Biology Organization (EMBO)
- Leducq Transatlantic Network ARTEMIS
- EMBO
- Marie Curie FP7 postdoctoral fellowship
- MRC [G0501711, G1002033] Funding Source: UKRI
- Medical Research Council [G1002033, G0501711] Funding Source: researchfish
Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and Foxc2(+/-); Vegfr3(+/-) compound heterozygosity recapitulated homozygous loss of Vegfr3. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.
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