Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2
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,...
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MDPI
2018
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| Online Access: | https://eprints.nottingham.ac.uk/51835/ |
| _version_ | 1848798585543458816 |
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| author | Peach, Chloe Mignone, Viviane Arruda, Maria Alcobia, Diana Hill, Stephen Kilpatrick, Laura Woolard, Jeanette |
| author_facet | Peach, Chloe Mignone, Viviane Arruda, Maria Alcobia, Diana Hill, Stephen Kilpatrick, Laura Woolard, Jeanette |
| author_sort | Peach, Chloe |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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 |
| first_indexed | 2025-11-14T20:22:07Z |
| format | Article |
| id | nottingham-51835 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:22:07Z |
| publishDate | 2018 |
| publisher | MDPI |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-518352020-05-04T19:33:54Z https://eprints.nottingham.ac.uk/51835/ 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 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 MDPI 2018-04-28 Article PeerReviewed Peach, Chloe, Mignone, Viviane, Arruda, Maria, Alcobia, Diana, Hill, Stephen, Kilpatrick, Laura and Woolard, Jeanette (2018) Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2. International Journal of Molecular Sciences, 19 (4). 1264/1-1264/27. ISSN 1422-0067 angiogenesis; endothelial cells; blood vessel; splicing; receptor tyrosine kinase inhibitors http://www.mdpi.com/1422-0067/19/4/1264 doi:10.3390/ijms19041264 doi:10.3390/ijms19041264 |
| spellingShingle | angiogenesis; endothelial cells; blood vessel; splicing; receptor tyrosine kinase inhibitors Peach, Chloe Mignone, Viviane Arruda, Maria Alcobia, Diana Hill, Stephen Kilpatrick, Laura Woolard, Jeanette Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2 |
| title | Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2 |
| title_full | Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2 |
| title_fullStr | Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2 |
| title_full_unstemmed | Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2 |
| title_short | Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2 |
| title_sort | molecular pharmacology of vegf-a isoforms: binding and signalling at vegfr2 |
| topic | angiogenesis; endothelial cells; blood vessel; splicing; receptor tyrosine kinase inhibitors |
| url | https://eprints.nottingham.ac.uk/51835/ https://eprints.nottingham.ac.uk/51835/ https://eprints.nottingham.ac.uk/51835/ |