Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland.
Nat Cell Biol. 2011 Sep 11;13(10):1202-13. doi: 10.1038/ncb2331.
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.
血管生成,即新血管的生长,涉及内皮细胞向尖端细胞和柄细胞的特化,这由 Notch 信号通路控制,而血管内皮生长因子受体 (VEGFR)-2 和 VEGFR-3 已被牵连到血管生成发芽中。令人惊讶的是,我们发现内皮细胞中 Vegfr3 的缺失(而非 VEGFR-3 阻断抗体)会导致出生后过度的血管生成发芽和分支,并降低 Notch 信号通路的水平,表明 VEGFR-3 具有被动和主动的信号转导方式。此外,表达 VEGFR-3 和 VEGFR-2 配体 VEGF-C 的巨噬细胞定位于血管分支点,而 Vegfc 杂合子小鼠表现出血管生成效率降低的特征,表现为血管分支减少。FoxC2 是 Notch 配体和靶基因表达的已知调节剂,而 Foxc2(+/-);Vegfr3(+/-) 复合杂合子重现了 Vegfr3 的纯合缺失。这些结果表明,巨噬细胞衍生的 VEGF-C 激活尖端细胞中的 VEGFR-3 以增强 Notch 信号通路,这有助于血管芽融合点处内皮细胞的表型转化。
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