2. Academic Validation
  3. Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2

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

  • Int J Mol Sci. 2018 Apr 23;19(4):1264. doi: 10.3390/ijms19041264.
Chloe J Peach 1 2,  Viviane W Mignone 3 4 5,  Maria Augusta Arruda 6 7 8,  Diana C Alcobia 9 10,  Stephen J Hill 11 12,  Laura E Kilpatrick 13 14,  Jeanette Woolard 15 16
Affiliations

Affiliations

  • 1 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. [email protected].
  • 2 Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, UK. [email protected].
  • 3 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. [email protected].
  • 4 Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, UK. [email protected].
  • 5 CAPES-University of Nottingham Programme in Drug Discovery, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. [email protected].
  • 6 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. [email protected].
  • 7 Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, UK. [email protected].
  • 8 CAPES-University of Nottingham Programme in Drug Discovery, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. [email protected].
  • 9 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. [email protected].
  • 10 Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, UK. [email protected].
  • 11 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. [email protected].
  • 12 Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, UK. [email protected].
  • 13 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. [email protected].
  • 14 Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, UK. [email protected].
  • 15 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. [email protected].
  • 16 Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, UK. [email protected].
PMID: 29690653 DOI: 10.3390/ijms19041264
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/Flt-1 and VEGFR2/KDR/Flk-1, they primarily signal via VEGFR2/KDR/Flk-1 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/KDR/Flk-1 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2/KDR/Flk-1, 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.

Keywords

angiogenesis; blood vessel; endothelial cells; receptor tyrosine kinase inhibitors; splicing.

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