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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 W Ahmad, Shakil Wang, Ke-Qing Cai, Meng Al-Ani, Bahjat Fujisawa, Takeshi Ma, Bin Sissaoui, Samir Ramma, Wenda
Cudmore, Melissa J
Hewett, Peter W
Ahmad, Shakil
Wang, Ke-Qing
Cai, Meng
Al-Ani, Bahjat
Fujisawa, Takeshi
Ma, Bin
Sissaoui, Samir
Ramma, Wenda
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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.
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The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. 2012, 3:972 Nat Commun
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2041-1723
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Archived with thanks to Nature communications