Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2

• Published in: International journal of molecular sciences 2018-04, Vol.19 (4), p.1264
• Main Authors: Peach, Chloe J, Mignone, Viviane W, Arruda, Maria Augusta, Alcobia, Diana C, Hill, Stephen J, Kilpatrick, Laura E, Woolard, Jeanette
• Format: Article
• Language: English
• Subjects: Alternative splicing; Angiogenesis; Animals; Binding; Bioavailability; Cancer; Cardiovascular disease; Cell proliferation; Drug discovery; Endothelial cells; Endothelial Cells - metabolism; Exons; Extracellular matrix; Genes; Growth factors; Humans; Isoforms; Kinases; Macular degeneration; Molecular modelling; Neuropilin; Permeability; Pharmacology; Physiology; Protein Isoforms - metabolism; Protein-tyrosine kinase receptors; Proteins; Review; Signal Transduction - physiology; Smooth muscle; Splicing; Tyrosine; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular endothelial growth factor receptors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19041264

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 gene at exon 8, resulting in VEGF a or VEGF b 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" VEGF a. 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.