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Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2

Peach, Chloe; Mignone, Viviane; Arruda, Maria; Alcobia, Diana; Hill, Stephen; Kilpatrick, Laura; Woolard, Jeanette

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Authors

Chloe Peach

Viviane Mignone

Maria Arruda

Diana Alcobia

STEPHEN HILL STEVE.HILL@NOTTINGHAM.AC.UK
Professor of Molecular Pharmacology

JEANETTE WOOLARD Jeanette.Woolard@nottingham.ac.uk
Professor of Cardiovascular Physiology and Pharmacology



Abstract

Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGFxxxa or VEGFxxxb isoforms. Alternative splicing events at exons 5–7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1. This review explores the molecular pharmacology of VEGF-A isoforms at VEGFR2 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2, this review re-evaluates the typical classification of these isoforms relative to the prototypical, “pro-angiogenic” VEGF165a. We also examine the molecular mechanisms underpinning the regulation of VEGF-A isoform signalling and the importance of interactions with other membrane and extracellular matrix proteins. As approved therapeutics targeting the VEGF-A/VEGFR signalling axis largely lack long-term efficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology. View Full-Text

Citation

Peach, C., Mignone, V., Arruda, M., Alcobia, D., Hill, S., Kilpatrick, L., & Woolard, J. (2018). Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2. International Journal of Molecular Sciences, 19(4), Article 1264. https://doi.org/10.3390/ijms19041264

Journal Article Type Article
Acceptance Date Apr 16, 2018
Publication Date Apr 28, 2018
Deposit Date May 16, 2018
Publicly Available Date Mar 29, 2024
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Electronic ISSN 1422-0067
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 19
Issue 4
Article Number 1264
DOI https://doi.org/10.3390/ijms19041264
Keywords angiogenesis; endothelial cells; blood vessel; splicing; receptor tyrosine kinase inhibitors
Public URL https://nottingham-repository.worktribe.com/output/929024
Publisher URL http://www.mdpi.com/1422-0067/19/4/1264

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