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

Melissa J Cudmore, Peter 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

Research output: Contribution to journalArticlepeer-review

86 Citations (Scopus)

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 languageEnglish
Pages (from-to)972
JournalNature Communications
Volume3
DOIs
Publication statusPublished - 2012

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