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

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.

Authors

R.P. Hulse

N. Beazley-Long

J. Hua

H. Kennedy

J. Prager

H. Bevan

Y. Qiu

E.S. Fernandes

M.V. Gammons

K. Ballmer-Hofer

A.C. Gittenberger de Groot

A.J. Churchill

S.J. Harper

S.D. Brain

DAVID BATES David.Bates@nottingham.ac.uk
Professor of Oncology

L.F. Donaldson



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 proangiogenic 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.

Citation

Hulse, R., Beazley-Long, N., Hua, J., Kennedy, H., Prager, J., Bevan, H., …Donaldson, L. (2014). Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia. Neurobiology of Disease, 71, 245-259. https://doi.org/10.1016/j.nbd.2014.08.012

Journal Article Type Article
Acceptance Date Aug 6, 2014
Online Publication Date Aug 21, 2014
Publication Date 2014-11
Deposit Date Jan 22, 2018
Publicly Available Date Mar 29, 2024
Print ISSN 0969-9961
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 71
Pages 245-259
DOI https://doi.org/10.1016/j.nbd.2014.08.012
Keywords Vascular endothelial growth factor A; Alternative mRNA splicing; Neuropathy; Nociceptors
Public URL https://nottingham-repository.worktribe.com/output/1104991
Publisher URL https://www.sciencedirect.com/science/article/pii/S0969996114002435?via%3Dihub
PMID 00034254

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