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 and Asif Ahmed ()
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Melissa J. Cudmore: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh
Peter W. Hewett: Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham
Shakil Ahmad: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh
Ke-Qing Wang: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh
Meng Cai: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh
Bahjat Al-Ani: College of Medicine, King Khalid University
Takeshi Fujisawa: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh
Bin Ma: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh
Samir Sissaoui: Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham
Wenda Ramma: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh
Mark R. Miller: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh
David E. Newby: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh
Yuchun Gu: IMM, Peking University
Bernhard Barleon: RELIATech, Inhoffenstraße 7
Herbert Weich: Helmholtz Centre for Infection Research
Asif Ahmed: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: 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) (VEGFR1−2) in endothelial cells with a synthetic ligand that binds specifically to VEGFR1−2. The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR1−2 activation mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation and vasorelaxation via the nitric oxide pathway. VEGFR1−2 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 VEGFR1−2 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.

Date: 2012
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DOI: 10.1038/ncomms1977

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