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

NEUROBIOLOGY OF DISEASE

卷:71

Article

Hulse, R. P.^1,6  Beazley-Long, N.^1,7  Hua, J.¹  Kennedy, H.¹  Prager, J.¹  Bevan, H.¹  Qiu, Y.¹  Fernandes, E. S.²  Gammons, M. V.¹  Ballmer-Hofer, K.³  de Groot, A. C. Gittenberger⁴  Churchill, A. J.⁵  Harper, S. J.¹  Brain, S. D.²  Bates, D. O.⁶  Donaldson, L. F.^1,7 

[1] Univ Bristol, Bristol BS8 1TD, Avon, England

[2] Kings Coll London, London SE1 9NH, England

[3] Paul Scherrer Inst, CH-5232 Villigen, Switzerland

[4] Leiden Univ, Med Ctr, NL-2300 RC Leiden, Netherlands

[5] Univ Bristol, Bristol BS1 2LX, Avon, England

[6] Univ Nottingham, Queens Med Ctr, Sch Med, Div Canc & Stem Cells, Nottingham NG2 7UH, England

[7] Univ Nottingham, Queens Med Ctr, Sch Med, Sch Life Sci, Nottingham NG2 7UH, England

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

DOI  :  10.1016/j.nbd.2014.08.012

来源: Elsevier

【 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-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.

【 授权许可】

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