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

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: College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences > Aston Medical School > Translational Medicine Research Group (TMRG)
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
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2017-01
Published Online Date: 2016-11-22
Accepted Date: 2016-11-20
Submitted Date: 2016-05-30
Authors: Cai, Meng (ORCID Profile 0000-0002-0864-667X)
Wang, Keqing (ORCID Profile 0000-0001-6239-6344)
Murdoch, Colin E. (ORCID Profile 0000-0002-0274-819X)
Gu, Yuchun (ORCID Profile 0000-0002-7558-0447)
Ahmed, Asif (ORCID Profile 0000-0002-8755-8546)

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