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

Neurobiology of Disease

N. Beazley-Long¹  H. Kennedy²  S.J. Harper³  S.D. Brain⁴  L.F. Donaldson⁵  K. Ballmer-Hofer⁵  A.J. Churchill⁶  H. Bevan⁷  Y. Qiu⁷  J. Hua⁷  E.S. Fernandes⁷  M.V. Gammons⁷  J. Prager⁷  A.C. Gittenberger de Groot⁷  R.P. Hulse⁷  D.O. Bates⁷ 

[1] Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UK;School of Life Sciences, The Medical School, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UK;Anatomy and Embryology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands;Clinical Sciences, University of Bristol, Bristol BS1 2LX, UK;King's College London, London SE1 9NH, UK;Paul Scherrer Institut, 5232 Villigen, Switzerland;Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK;

关键词: Vascular endothelial growth factor A;    Alternative mRNA splicing;    Neuropathy;    Nociceptors;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown