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 and Ahmed, Asif (2012). The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. Nature Communications, 3 ,

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.

Publication DOI: https://doi.org/10.1038/ncomms1977
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Aston Medical School
Additional Information: 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/
Uncontrolled Keywords: Biochemistry, Genetics and Molecular Biology(all),Chemistry(all),Physics and Astronomy(all)
Full Text Link: http://www.natu ... ncomms1977.html
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2012-07-24
Authors: Cudmore, Melissa J.
Hewett, Peter W.
Ahmad, Shakil ( 0000-0002-9294-0475)
Wang, Ke-Qing
Cai, Meng ( 0000-0002-0864-667X)
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

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