Heterodimerisation between VEGFR-1 and VEGFR-2 and not the homodimers of VEGFR-1 inhibit VEGFR-2 activity

Meng Cai, Keqing Wang, Colin E. Murdoch, Yuchun Gu, Asif Ahmed

Research output: Contribution to journalArticle

3 Citations (Scopus)
199 Downloads (Pure)

Abstract

Vascular endothelial growth factor (VEGF) signaling is tightly regulated by specific VEGF receptors (VEGF-R). Recently, we identified heterodimerisation between VEGFR-1 and VEGFR-2 (VEGFR1–2) to regulate VEGFR-2 function. However, both the mechanism of action and the relationship with VEGFR-1 homodimers remain unknown. The current study shows that activation of VEGFR1–2, but not VEGFR-1 homodimers, inhibits VEGFR-2 receptor phosphorylation under VEGF stimulation in human endothelial cells. Furthermore, inhibition of phosphatidylinositol 3-kinase (PI3K) increases VEGFR-2 phosphorylation under VEGF stimulation. More importantly, inhibition of PI3K pathway abolishes the VEGFR1–2 mediated inhibition of VEGFR-2 phosphorylation. We further demonstrate that inhibition of PI3K pathway promotes capillary tube formation. Finally, the inhibition of PI3K abrogates the inhibition of in vitro angiogenesis mediated by VEGFR1–2 heterodimers. These findings demonstrate that VEGFR1–2 heterodimers and not VEGFR-1 homodimers inhibit VEGF-VEGFR-2 signaling by suppressing VEGFR-2 phosphorylation via PI3K pathway.
Original languageEnglish
Pages (from-to)11-20
Number of pages10
JournalVascular Pharmacology
Volume88
Early online date22 Nov 2016
DOIs
Publication statusPublished - Jan 2017

Keywords

  • vascular endothelial growth factor
  • VEGF receptors
  • VEGF
  • heterodimers
  • phosphatidylinositol 3-kinase
  • PI3K
  • angiogenesis

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