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VEGFR-3 通过增强 Notch 信号控制血管融合部位的尖端到干转换。

VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.

机构信息

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.

出版信息

Nat Cell Biol. 2011 Sep 11;13(10):1202-13. doi: 10.1038/ncb2331.


DOI:10.1038/ncb2331
PMID:21909098
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3261765/
Abstract

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.

摘要

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。

相似文献

[1]
VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.

Nat Cell Biol. 2011-9-11

[2]
Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.

Nature. 2012-3-18

[3]
VEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling.

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[4]
Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation.

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[5]
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[6]
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[7]
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Am J Pathol. 2009-10-1

[8]
VEGFRs and Notch: a dynamic collaboration in vascular patterning.

Biochem Soc Trans. 2009-12

[9]
Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis.

Circ Res. 2014-4-22

[10]
Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.

Circ Res. 2010-7-8

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本文引用的文献

[1]
Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor.

Blood. 2011-5-12

[2]
Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization.

Cancer Cell. 2010-12-2

[3]
Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting.

Nat Cell Biol. 2010-9-26

[4]
VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis.

Cell Res. 2010-8-10

[5]
Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis.

Nature. 2010-5-5

[6]
Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.

Nature. 2010-5-27

[7]
Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development.

Genes Dev. 2010-5

[8]
Endothelial cell adhesion to the extracellular matrix induces c-Src-dependent VEGFR-3 phosphorylation without the activation of the receptor intrinsic kinase activity.

Circ Res. 2010-4-29

[9]
Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction.

Blood. 2010-4-19

[10]
Convergence of Notch and beta-catenin signaling induces arterial fate in vascular progenitors.

J Cell Biol. 2010-4-19

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