2.50
HDL Handle:
http://hdl.handle.net/10033/251812
Title:
The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis.
Authors:
Cudmore, Melissa J; Hewett, Peter W; Ahmad, Shakil; Wang, Ke-Qing; Cai, Meng; Al-Ani, Bahjat; Fujisawa, Takeshi; Ma, Bin; Sissaoui, Samir; Ramma, Wenda; Miller, Mark R; Newby, David E; Gu, Yuchun; Barleon, Bernhard; Weich, Herbert; Ahmed, Asif
Abstract:
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.
Affiliation:
University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Citation:
The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. 2012, 3:972 Nat Commun
Journal:
Nature communications
Issue Date:
2012
URI:
http://hdl.handle.net/10033/251812
DOI:
10.1038/ncomms1977
PubMed ID:
22828632
Type:
Article
Language:
en
ISSN:
2041-1723
Appears in Collections:
Publications of Dept. Gene Regulation and Differentiation (RDIF)

Full metadata record

DC FieldValueLanguage
dc.contributor.authorCudmore, Melissa Jen_GB
dc.contributor.authorHewett, Peter Wen_GB
dc.contributor.authorAhmad, Shakilen_GB
dc.contributor.authorWang, Ke-Qingen_GB
dc.contributor.authorCai, Mengen_GB
dc.contributor.authorAl-Ani, Bahjaten_GB
dc.contributor.authorFujisawa, Takeshien_GB
dc.contributor.authorMa, Binen_GB
dc.contributor.authorSissaoui, Samiren_GB
dc.contributor.authorRamma, Wendaen_GB
dc.contributor.authorMiller, Mark Ren_GB
dc.contributor.authorNewby, David Een_GB
dc.contributor.authorGu, Yuchunen_GB
dc.contributor.authorBarleon, Bernharden_GB
dc.contributor.authorWeich, Herberten_GB
dc.contributor.authorAhmed, Asifen_GB
dc.date.accessioned2012-11-12T12:02:48Z-
dc.date.available2012-11-12T12:02:48Z-
dc.date.issued2012-
dc.identifier.citationThe role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. 2012, 3:972 Nat Communen_GB
dc.identifier.issn2041-1723-
dc.identifier.pmid22828632-
dc.identifier.doi10.1038/ncomms1977-
dc.identifier.urihttp://hdl.handle.net/10033/251812-
dc.description.abstractVEGF-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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Nature communicationsen_GB
dc.subject.meshBlotting, Westernen_GB
dc.subject.meshCells, Cultureden_GB
dc.subject.meshEndothelial Cellsen_GB
dc.subject.meshEnzyme-Linked Immunosorbent Assayen_GB
dc.subject.meshFlow Cytometryen_GB
dc.subject.meshHumansen_GB
dc.subject.meshImmunoprecipitationen_GB
dc.subject.meshProtein Multimerizationen_GB
dc.subject.meshRNA, Small Interferingen_GB
dc.subject.meshVascular Endothelial Growth Factor Receptor-1en_GB
dc.subject.meshVascular Endothelial Growth Factor Receptor-2en_GB
dc.titleThe role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis.en
dc.typeArticleen
dc.contributor.departmentUniversity/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.en_GB
dc.identifier.journalNature communicationsen_GB
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