Academic Journal
Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia
| Title: | Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia |
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| 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, D.O. Bates, L.F. Donaldson |
| Source: | Neurobiology of Disease, Vol 71, Iss , Pp 245-259 (2014) |
| Publisher Information: | Elsevier, 2014. |
| Publication Year: | 2014 |
| Collection: | LCC:Neurosciences. Biological psychiatry. Neuropsychiatry |
| Subject Terms: | Vascular endothelial growth factor A, Alternative mRNA splicing, Neuropathy, Nociceptors, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1095-953X 63569434 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S0969996114002435; https://doaj.org/toc/1095-953X |
| DOI: | 10.1016/j.nbd.2014.08.012 |
| Access URL: | https://doaj.org/article/bc507aa63569434b8999d0b9a03067d9 |
| Accession Number: | edsdoj.bc507aa63569434b8999d0b9a03067d9 |
| Database: | Directory of Open Access Journals |
| ISSN: | 1095953X 63569434 |
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| DOI: | 10.1016/j.nbd.2014.08.012 |
| Published in: | Neurobiology of Disease |
| Language: | English |