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

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The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. / Cudmore, Melissa J; Hewett, Peter; 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, 2012, p. 972.

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@article{996b4b1a49264381b45ab2955ee12b0e,
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 Peter Hewett 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",
year = "2012",
doi = "10.1038/ncomms1977",
language = "English",
volume = "3",
pages = "972",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Springer",

}

RIS

TY - JOUR

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

AU - Cudmore, Melissa J

AU - Hewett, Peter

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

PY - 2012

Y1 - 2012

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.

U2 - 10.1038/ncomms1977

DO - 10.1038/ncomms1977

M3 - Article

C2 - 22828632

VL - 3

SP - 972

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

ER -