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

• Published in: Neurobiology of disease Vol. 71; pp. 245 - 259
• Main Authors: Hulse, R.P, Beazley-Long, N, Hua, J, Kennedy, H, Prager, J, Bevan, H, Qiu, Y, Fernandes, E.S, Gammons, M.V, Ballmer-Hofer, K, Gittenberger de Groot, A.C, Churchill, A.J, Harper, S.J, Brain, S.D, Bates, D.O, Donaldson, L.F
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2014; Academic Press; Elsevier
• Subjects: Alternative mRNA splicing; Animals; Antibodies - pharmacology; Antibodies - therapeutic use; Benzofurans; Disease Models, Animal; DNA, Recombinant - genetics; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Ganglia, Spinal - cytology; Hyperalgesia - metabolism; Male; Mice; Mice, Transgenic; Neural Conduction - genetics; Neuralgia - metabolism; Neuralgia - therapy; Neurology; Neuropathy; Nociceptors; Pain Measurement; Pain Threshold - physiology; Quinolines; Rats; Rats, Wistar; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism; TRPV Cation Channels - deficiency; TRPV Cation Channels - genetics; Vascular endothelial growth factor A; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - immunology; Vascular Endothelial Growth Factor A - metabolism; VEGFR2; vascular endothelial growth factor receptor 2; serine arginine protein kinase 1; isolectin B4; SRSF1; transient receptor potential vanilloid 1; dorsal root ganglia; vascular endothelial growth factor-A; serine arginine splice factor 1; TRPV1; Neuropathy; VEGF-A; partial saphenous nerve ligation injury; Alternative mRNA splicing; SRPK1; CV; Vascular endothelial growth factor A; conduction velocity; DRG; Nociceptors; IB4; PSNI
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2014.08.012

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-A165 a and VEGF-A165 b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165 a is upregulated and predominates over the VEGF-A165 b isoform. We show here that in rats and mice VEGF-A165 a and VEGF-A165 b have opposing effects on pain, and that blocking the proximal splicing event – leading to the preferential expression of VEGF-A165 b over VEGF165 a – prevents pain in vivo. VEGF-A165 a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165 b blocks the effect of VEGF-A165 a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxx a compared to VEGF-Axxx b, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxx a expression and reversed associated neuropathic pain. Exogenous VEGF-A165 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-Axxx a/VEGF-Axxx b balance by targeting alternative RNA splicing may be a new analgesic strategy.