The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis

Melissa J. Cudmore, Peter W. Hewett, Shakil Ahmad, Ke-Qing Wang, Meng Cai, Bahjat Al-Ani, Takeshi Fujisawa, Bin Ma, Samir Sissaoui, Wenda Ramma, Mark R. Miller, David E. Newby, Yuchun Gu, Bernhard Barleon, Herbert Weich, Asif Ahmed

Research output: Contribution to journalArticle

Abstract

VEGF-A activity is tightly regulated by ligand and receptor availability. Here we investigate the physiological function of heterodimers between VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (KDR; Flk-1) (VEGFR(1-2)) in endothelial cells with a synthetic ligand that binds specifically to VEGFR(1-2). The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR(1-2) activation mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation and vasorelaxation via the nitric oxide pathway. VEGFR(1-2) activation does not mediate proliferation or elicit endothelial tissue factor production, confirming that these functions are controlled by VEGFR-2 homodimers. We further demonstrate that activation of VEGFR(1-2) inhibits VEGF-A-induced prostacyclin release, phosphorylation of ERK1/2 MAP kinase and mobilization of intracellular calcium from primary endothelial cells. These findings indicate that VEGFR-1 subunits modulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits and such heterodimers regulate endothelial cell homeostasis.
LanguageEnglish
Article number972
JournalNature Communications
Volume3
DOIs
Publication statusPublished - 24 Jul 2012

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Vascular Endothelial Growth Factor Receptor-1
homeostasis
Vascular Endothelial Growth Factor Receptor-2
Endothelial cells
Homeostasis
Endothelial Cells
phosphorylation
activation
ligands
monomers
Vascular Endothelial Growth Factor A
Phosphorylation
Chemical activation
nitric oxide
Ligands
availability
calcium
Monomers
tubes
Vascular Endothelial Growth Factor Receptor

Bibliographical note

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

Cite this

Cudmore, Melissa J. ; Hewett, Peter W. ; Ahmad, Shakil ; Wang, Ke-Qing ; Cai, Meng ; Al-Ani, Bahjat ; Fujisawa, Takeshi ; Ma, Bin ; Sissaoui, Samir ; Ramma, Wenda ; Miller, Mark R. ; Newby, David E. ; Gu, Yuchun ; Barleon, Bernhard ; Weich, Herbert ; Ahmed, Asif. / The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. In: Nature Communications. 2012 ; Vol. 3.
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title = "The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis",
abstract = "VEGF-A activity is tightly regulated by ligand and receptor availability. Here we investigate the physiological function of heterodimers between VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (KDR; Flk-1) (VEGFR(1-2)) in endothelial cells with a synthetic ligand that binds specifically to VEGFR(1-2). The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR(1-2) activation mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation and vasorelaxation via the nitric oxide pathway. VEGFR(1-2) activation does not mediate proliferation or elicit endothelial tissue factor production, confirming that these functions are controlled by VEGFR-2 homodimers. We further demonstrate that activation of VEGFR(1-2) inhibits VEGF-A-induced prostacyclin release, phosphorylation of ERK1/2 MAP kinase and mobilization of intracellular calcium from primary endothelial cells. These findings indicate that VEGFR-1 subunits modulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits and such heterodimers regulate endothelial cell homeostasis.",
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Cudmore, MJ, Hewett, PW, Ahmad, S, Wang, K-Q, Cai, M, Al-Ani, B, Fujisawa, T, Ma, B, Sissaoui, S, Ramma, W, Miller, MR, Newby, DE, Gu, Y, Barleon, B, Weich, H & Ahmed, A 2012, 'The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis' Nature Communications, vol. 3, 972. https://doi.org/10.1038/ncomms1977, https://doi.org/10.1038/ncomms1977

The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. / Cudmore, Melissa J.; Hewett, Peter W.; Ahmad, Shakil; Wang, Ke-Qing; Cai, Meng; Al-Ani, Bahjat; Fujisawa, Takeshi; Ma, Bin; Sissaoui, Samir; Ramma, Wenda; Miller, Mark R.; Newby, David E.; Gu, Yuchun; Barleon, Bernhard; Weich, Herbert; Ahmed, Asif.

In: Nature Communications, Vol. 3, 972, 24.07.2012.

Research output: Contribution to journalArticle

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T1 - The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis

AU - Cudmore, Melissa J.

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AU - Ahmad, Shakil

AU - Wang, Ke-Qing

AU - Cai, Meng

AU - Al-Ani, Bahjat

AU - Fujisawa, Takeshi

AU - Ma, Bin

AU - Sissaoui, Samir

AU - Ramma, Wenda

AU - Miller, Mark R.

AU - Newby, David E.

AU - Gu, Yuchun

AU - Barleon, Bernhard

AU - Weich, Herbert

AU - Ahmed, Asif

N1 - This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

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N2 - VEGF-A activity is tightly regulated by ligand and receptor availability. Here we investigate the physiological function of heterodimers between VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (KDR; Flk-1) (VEGFR(1-2)) in endothelial cells with a synthetic ligand that binds specifically to VEGFR(1-2). The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR(1-2) activation mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation and vasorelaxation via the nitric oxide pathway. VEGFR(1-2) activation does not mediate proliferation or elicit endothelial tissue factor production, confirming that these functions are controlled by VEGFR-2 homodimers. We further demonstrate that activation of VEGFR(1-2) inhibits VEGF-A-induced prostacyclin release, phosphorylation of ERK1/2 MAP kinase and mobilization of intracellular calcium from primary endothelial cells. These findings indicate that VEGFR-1 subunits modulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits and such heterodimers regulate endothelial cell homeostasis.

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