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

Cai, Meng; Wang, Keqing; Murdoch, Colin E.; Gu, Yuchun and Ahmed, Asif (2017). Heterodimerisation between VEGFR-1 and VEGFR-2 and not the homodimers of VEGFR-1 inhibit VEGFR-2 activity. Vascular Pharmacology, 88 , pp. 11-20.

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.

Publication DOI: https://doi.org/10.1016/j.vph.2016.11.007
Divisions: Aston Medical School
Related URLs:
Additional Information: © 2016, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ Funding: British Heart Foundation (RG/09/001/25940); MRC (G0700288); Royal Society and European Union
Uncontrolled Keywords: vascular endothelial growth factor,VEGF receptors,VEGF,heterodimers,phosphatidylinositol 3-kinase,PI3K,angiogenesis,Physiology,Molecular Medicine,Pharmacology
Published Date: 2017-01

Download

[img]

Version: Submitted Version

| Preview

Export / Share Citation


Statistics

Additional statistics for this record