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.
authors: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors: Melissa J
authors: MJ
authors: Cudmore
authors: Peter W
authors: PW
authors: Hewett
authors: Shakil
authors: S
authors: Ahmad
authors: Ke-Qing
authors: KQ
authors: Wang
authors: Meng
authors: M
authors: Cai
authors: Bahjat
authors: B
authors: Al-Ani
authors: Takeshi
authors: T
authors: Fujisawa
authors: Bin
authors: B
authors: Ma
authors: Samir
authors: S
authors: Sissaoui
authors: Wenda
authors: W
authors: Ramma
authors: Mark R
authors: MR
authors: Miller
authors: David E
authors: DE
authors: Newby
authors: Yuchun
authors: Y
authors: Gu
authors: Bernhard
authors: B
authors: Barleon
authors: Herbert
authors: H
authors: Weich
authors: Asif
authors: A
authors: Ahmed
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2