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

Tuomas Tammela; Georgia Zarkada; Harri Nurmi; Lars Jakobsson; Krista Heinolainen; Denis Tvorogov; Wei Zheng; Claudio A Franco; Aino Murtomäki; Evelyn Aranda; Naoyuki Miura; Seppo Ylä-Herttuala; Marcus Fruttiger; Taija Mäkinen; Anne Eichmann; Jeffrey W Pollard; Holger Gerhardt; Kari Alitalo

doi:10.1038/ncb2331

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

Tuomas Tammela, Georgia Zarkada, Harri Nurmi, Lars Jakobsson, Krista Heinolainen, Denis Tvorogov, Wei Zheng, Claudio A Franco, Aino Murtomäki, Evelyn Aranda, Naoyuki Miura, Seppo Ylä-Herttuala, Marcus Fruttiger, Taija Mäkinen, Anne Eichmann, Jeffrey W Pollard, Holger Gerhardt, Kari Alitalo

Deanery of Clinical Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1202-13
Number of pages	12
Journal	Nature Cell Biology
Volume	13
Issue number	10
DOIs	https://doi.org/10.1038/ncb2331
Publication status	Published - Oct 2011

Keywords / Materials (for Non-textual outputs)

Animals
Antibodies
Cell Line, Tumor
Endothelial Cells
Forkhead Transcription Factors
Gene Expression Regulation
Human Umbilical Vein Endothelial Cells
Humans
Macrophages
Mice
Mice, Knockout
Neovascularization, Pathologic
Neovascularization, Physiologic
Phosphatidylinositol 3-Kinase
Protein Kinase Inhibitors
RNA Interference
Receptors, Notch
Retinal Vessels
Rhombencephalon
Signal Transduction
Time Factors
Transduction, Genetic
Transfection
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor B
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor D
Vascular Endothelial Growth Factor Receptor-3

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10.1038/ncb2331

VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signallingAccepted author manuscript, 3.29 MB

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Tammela, T., Zarkada, G., Nurmi, H., Jakobsson, L., Heinolainen, K., Tvorogov, D., Zheng, W., Franco, C. A., Murtomäki, A., Aranda, E., Miura, N., Ylä-Herttuala, S., Fruttiger, M., Mäkinen, T., Eichmann, A., Pollard, J. W., Gerhardt, H., & Alitalo, K. (2011). VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nature Cell Biology, 13(10), 1202-13. https://doi.org/10.1038/ncb2331

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title = "VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling",

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.",

keywords = "Animals, Antibodies, Cell Line, Tumor, Endothelial Cells, Forkhead Transcription Factors, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells, Humans, Macrophages, Mice, Mice, Knockout, Neovascularization, Pathologic, Neovascularization, Physiologic, Phosphatidylinositol 3-Kinase, Protein Kinase Inhibitors, RNA Interference, Receptors, Notch, Retinal Vessels, Rhombencephalon, Signal Transduction, Time Factors, Transduction, Genetic, Transfection, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor B, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor D, Vascular Endothelial Growth Factor Receptor-3",

author = "Tuomas Tammela and Georgia Zarkada and Harri Nurmi and Lars Jakobsson and Krista Heinolainen and Denis Tvorogov and Wei Zheng and Franco, {Claudio A} and Aino Murtom{\"a}ki and Evelyn Aranda and Naoyuki Miura and Seppo Yl{\"a}-Herttuala and Marcus Fruttiger and Taija M{\"a}kinen and Anne Eichmann and Pollard, {Jeffrey W} and Holger Gerhardt and Kari Alitalo",

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Tammela, T, Zarkada, G, Nurmi, H, Jakobsson, L, Heinolainen, K, Tvorogov, D, Zheng, W, Franco, CA, Murtomäki, A, Aranda, E, Miura, N, Ylä-Herttuala, S, Fruttiger, M, Mäkinen, T, Eichmann, A, Pollard, JW, Gerhardt, H & Alitalo, K 2011, 'VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling', Nature Cell Biology, vol. 13, no. 10, pp. 1202-13. https://doi.org/10.1038/ncb2331

TY - JOUR

T1 - VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling

AU - Tammela, Tuomas

AU - Zarkada, Georgia

AU - Nurmi, Harri

AU - Jakobsson, Lars

AU - Heinolainen, Krista

AU - Tvorogov, Denis

AU - Zheng, Wei

AU - Franco, Claudio A

AU - Murtomäki, Aino

AU - Aranda, Evelyn

AU - Miura, Naoyuki

AU - Ylä-Herttuala, Seppo

AU - Fruttiger, Marcus

AU - Mäkinen, Taija

AU - Eichmann, Anne

AU - Pollard, Jeffrey W

AU - Gerhardt, Holger

AU - Alitalo, Kari

PY - 2011/10

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N2 - 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.

AB - 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.

KW - Animals

KW - Antibodies

KW - Cell Line, Tumor

KW - Endothelial Cells

KW - Forkhead Transcription Factors

KW - Gene Expression Regulation

KW - Human Umbilical Vein Endothelial Cells

KW - Humans

KW - Macrophages

KW - Mice

KW - Mice, Knockout

KW - Neovascularization, Pathologic

KW - Neovascularization, Physiologic

KW - Phosphatidylinositol 3-Kinase

KW - Protein Kinase Inhibitors

KW - RNA Interference

KW - Receptors, Notch

KW - Retinal Vessels

KW - Rhombencephalon

KW - Signal Transduction

KW - Time Factors

KW - Transduction, Genetic

KW - Transfection

KW - Vascular Endothelial Growth Factor A

KW - Vascular Endothelial Growth Factor B

KW - Vascular Endothelial Growth Factor C

KW - Vascular Endothelial Growth Factor D

KW - Vascular Endothelial Growth Factor Receptor-3

U2 - 10.1038/ncb2331

DO - 10.1038/ncb2331

M3 - Article

C2 - 21909098

SN - 1465-7392

VL - 13

SP - 1202

EP - 1213

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 10

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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