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

Hulse, R.P. ORCID: 0000-0002-5193-9822, 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. and Donaldson, L.F., 2014. Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia. Neurobiology of Disease, 71, pp. 245-259. ISSN 0969-9961

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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.

Item Type: Journal article
Publication Title: Neurobiology of Disease
Creators: 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. and Donaldson, L.F.
Publisher: Academic Press
Date: November 2014
Volume: 71
ISSN: 0969-9961
Identifiers:
NumberType
10.1016/j.nbd.2014.08.012DOI
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 09 Jan 2018 16:03
Last Modified: 09 Jan 2018 16:03
URI: http://irep.ntu.ac.uk/id/eprint/32365

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