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

doi:10.1038/ncomms1977

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

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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.

Original language	English
Article number	972
Journal	Nature Communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms1977 https://doi.org/10.1038/ncomms1977
Publication status	Published - 24 Jul 2012

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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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The role of heterodimerization between VEGFR-1 and VEGFR-2
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/
Final published version, 1.16 MBLicence: CC BY-NC-SA 3.0

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Cudmore, M. J., Hewett, P. W., Ahmad, S., Wang, K.-Q., Cai, M., Al-Ani, B., Fujisawa, T., Ma, B., Sissaoui, S., Ramma, W., Miller, M. R., Newby, D. E., 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, 3, Article 972. https://doi.org/10.1038/ncomms1977, https://doi.org/10.1038/ncomms1977

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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.",

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

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/",

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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

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AU - Cudmore, Melissa J.

AU - Hewett, Peter W.

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/

PY - 2012/7/24

Y1 - 2012/7/24

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.

AB - 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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DO - 10.1038/ncomms1977

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JO - Nature Communications

JF - Nature Communications

M1 - 972

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

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