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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Antibodies / therapeutic use*
  • Benzofurans
  • DNA, Recombinant / genetics*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Ganglia, Spinal / cytology
  • Hyperalgesia / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Conduction / genetics
  • Neuralgia / metabolism*
  • Neuralgia / therapy*
  • Pain Measurement
  • Pain Threshold / physiology
  • Quinolines
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Rats
  • Rats, Wistar
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • TRPV Cation Channels / deficiency
  • TRPV Cation Channels / genetics
  • Vascular Endothelial Growth Factor A* / genetics
  • Vascular Endothelial Growth Factor A* / immunology
  • Vascular Endothelial Growth Factor A* / metabolism

Substances

  • (3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide
  • Antibodies
  • Benzofurans
  • DNA, Recombinant
  • Enzyme Inhibitors
  • Quinolines
  • RNA, Messenger
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Vascular Endothelial Growth Factor A