title: 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 VEGFR1-2mediated 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 VEGFR1-2heterodimers. These findings demonstrate that VEGFR1-2heterodimers and not VEGFR-1 homodimers inhibit VEGF-VEGFR-2 signaling by suppressing VEGFR-2 phosphorylation via PI3K pathway.
authors.affiliation: Aston Medical Research Institute, Aston Medical School, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
authors.forename: Meng
authors.initials: M
authors.lastname: Cai
authors.affiliation: Aston Medical Research Institute, Aston Medical School, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.affiliation: Aston Medical Research Institute, Aston Medical School, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
authors.forename: Colin E
authors.initials: CE
authors.lastname: Murdoch
authors.affiliation: Aston Medical Research Institute, Aston Medical School, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Aston Medical Research Institute, Aston Medical School, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom. Electronic address: asif.ahmed@aston.ac.uk.
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D018919:Neovascularization, Physiologic / Q000502:physiology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization; D015398:Signal Transduction; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D058539:Phosphatidylinositol 3-Kinase; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Heterodimers; Phosphatidylinositol 3-kinase (PI3K); VEGF receptors; Vascular endothelial growth factor (VEGF)