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Neurobiol Dis. 2014 Nov;71:245-59. doi: 10.1016/j.nbd.2014.08.012. Epub 2014 Aug 21.

Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia.

Author information

1
Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK; Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UK.
2
Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK; School of Life Sciences, The Medical School, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UK.
3
Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK.
4
King's College London, London SE1 9NH, UK.
5
Paul Scherrer Institut, 5232 Villigen, Switzerland.
6
Anatomy and Embryology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands.
7
Clinical Sciences, University of Bristol, Bristol BS1 2LX, UK.
8
Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UK. Electronic address: David.Bates@nottingham.ac.uk.
9
Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK; School of Life Sciences, The Medical School, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UK. Electronic address: Lucy.Donaldson@nottingham.ac.uk.

Abstract

Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165a and VEGF-A165b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165a is upregulated and predominates over the VEGF-A165b isoform. We show here that in rats and mice VEGF-A165a and VEGF-A165b have opposing effects on pain, and that blocking the proximal splicing event - leading to the preferential expression of VEGF-A165b over VEGF165a - prevents pain in vivo. VEGF-A165a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165b blocks the effect of VEGF-A165a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxxa compared to VEGF-Axxxb, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxxa expression and reversed associated neuropathic pain. Exogenous VEGF-A165b also ameliorated neuropathic pain. We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxxa/VEGF-Axxxb balance by targeting alternative RNA splicing may be a new analgesic strategy.

KEYWORDS:

Alternative mRNA splicing; Neuropathy; Nociceptors; Vascular endothelial growth factor A

PMID:
25151644
PMCID:
PMC4194316
DOI:
10.1016/j.nbd.2014.08.012
[Indexed for MEDLINE]
Free PMC Article
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