Journal Article

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

Cudmore, Melissa J., Gu, Yuchun, Barleon, Bernhard, Al-Ani, Bahjat, Newby, David E., Weich, Herbert, Sissaoui, Samir, Ahmed, Asif, Hewett, Peter W., Wang, Ke-Qing, Cai, Meng, Miller, Mark R., Fujisawa, Takeshi, Ramma, Wenda, Ahmad, Shakil, Ma, Bin

2012

Overview

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. Vascular endothelial growth factor receptors (VEGFRs) assemble in dimers, the composition of which is thought to influence their function. Here, Cudmore et al . create a synthetic ligand that specifically activates VEGFR-1:VEGFR-2 heterodimers and explore their role in regulating endothelial cell function.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/80/86 / 631/92 / Blotting, Western / Cells, Cultured / Endothelial Cells - metabolism / Enzyme-Linked Immunosorbent Assay / Flow Cytometry / Humanities and Social Sciences / Humans / Immunoprecipitation / multidisciplinary / Nitric oxide / Protein Multimerization / RNA, Small Interfering - genetics / Science / Science (multidisciplinary) / Vascular Endothelial Growth Factor Receptor-1 - genetics / Vascular Endothelial Growth Factor Receptor-1 - metabolism / Vascular Endothelial Growth Factor Receptor-2 - genetics / Vascular Endothelial Growth Factor Receptor-2 - metabolism