Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 19, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms19041264
Keywords
angiogenesis; endothelial cells; blood vessel; splicing; receptor tyrosine kinase inhibitors
Funding
- Centre of Membrane Proteins and Receptors (COMPARE), Biotechnology and Biological Sciences Research Council [BB/L019418/1, BB/L013827/1]
- Medical Research Council [MR/N020081/1]
- AJ Clark Scholarship from the British Pharmacological Society
- Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES)-University of Nottingham Programme in Drug Discovery Postdoctoral Fellowship [041/2014]
- BBSRC [BB/L019418/1, BB/L013827/1] Funding Source: UKRI
- MRC [MR/N020081/1] Funding Source: UKRI
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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 VEGF(xxx)a or VEGF(xxx)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 themolecular 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(165)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-termefficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology.
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