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

R P Hulse, N Beazley-Long, J Hua, H Kennedy, J Prager, H Bevan, Y Qiu, E S Fernandes, M V Gammons, K Ballmer-Hofer, A C Gittenberger de Groot, A J Churchill, S J Harper, S D Brain, D O Bates*, L F Donaldson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

33 Citations (Scopus)

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-A(165)a and VEGF-A(165)b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A(165)a is upregulated and predominates over the VEGF-A(165)b isoform.

We show here that in rats and mice VEGF-A(165)a and VEGF-A(165)b have opposing effects on pain, and that blocking the proximal splicing event - leading to the preferential expression of VEGF-A(165)b over VEGF(165)a - prevents pain in vivo. VEGF-A(165)a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A(165)b blocks the effect of VEGF-A(165)a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-A(xxx)a compared to VEGF-A(xxx)b, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-A(xxx)a expression and reversed associated neuropathic pain. Exogenous VEGF-A(165)b 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-A(xxx)a/VEGF-A(xxx)b balance by targeting alternative RNA splicing may be a new analgesic strategy. (C) 2014 University of Nottingham. Published by Elsevier Inc.

Original languageEnglish
Pages (from-to)245-259
Number of pages15
JournalNeurobiology of Disease
Volume71
Issue number1
Early online date21 Aug 2014
DOIs
Publication statusPublished - 1 Nov 2014

Keywords

  • Animals
  • Antibodies
  • Benzofurans
  • DNA, Recombinant
  • Disease Models, Animal
  • Enzyme Inhibitors
  • Ganglia, Spinal
  • Hyperalgesia
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Conduction
  • Neuralgia
  • Pain Measurement
  • Pain Threshold
  • Quinolines
  • RNA, Messenger
  • Rats
  • Rats, Wistar
  • Sensory Receptor Cells
  • TRPV Cation Channels
  • Vascular Endothelial Growth Factor A

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