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 language | English |
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Pages (from-to) | 245-259 |
Number of pages | 15 |
Journal | Neurobiology of Disease |
Volume | 71 |
Issue number | 1 |
Early online date | 21 Aug 2014 |
DOIs | |
Publication status | Published - 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