Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia
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...
Main Authors: | , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2014-11-01
|
Series: | Neurobiology of Disease |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114002435 |
id |
doaj-bc507aa63569434b8999d0b9a03067d9 |
---|---|
record_format |
Article |
spelling |
doaj-bc507aa63569434b8999d0b9a03067d92021-03-22T12:41:47ZengElsevierNeurobiology of Disease1095-953X2014-11-0171245259Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesiaR.P. Hulse0N. Beazley-Long1J. Hua2H. Kennedy3J. Prager4H. Bevan5Y. Qiu6E.S. Fernandes7M.V. Gammons8K. Ballmer-Hofer9A.C. Gittenberger de Groot10A.J. Churchill11S.J. Harper12S.D. Brain13D.O. Bates14L.F. Donaldson15Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK; Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UKPhysiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK; School of Life Sciences, The Medical School, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UKPhysiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UKPhysiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UKPhysiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UKPhysiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UKPhysiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UKKing's College London, London SE1 9NH, UKPhysiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UKPaul Scherrer Institut, 5232 Villigen, SwitzerlandAnatomy and Embryology, Leiden University Medical Centre, 2300 RC Leiden, The NetherlandsClinical Sciences, University of Bristol, Bristol BS1 2LX, UKPhysiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UKKing's College London, London SE1 9NH, UKCancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UK; Corresponding author.Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK; School of Life Sciences, The Medical School, University of Nottingham, Queen's Medical Centre, Nottingham NG2 7UH, UK; Correspondence to: L.F. Donaldson, School of Life Sciences, University of Nottingham, The Medical School QMC, Nottingham NG7 2UH, UK.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.http://www.sciencedirect.com/science/article/pii/S0969996114002435Vascular endothelial growth factor AAlternative mRNA splicingNeuropathyNociceptors |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia Neurobiology of Disease Vascular endothelial growth factor A Alternative mRNA splicing Neuropathy Nociceptors |
author_facet |
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 |
author_sort |
R.P. Hulse |
title |
Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia |
title_short |
Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia |
title_full |
Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia |
title_fullStr |
Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia |
title_full_unstemmed |
Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia |
title_sort |
regulation of alternative vegf-a mrna splicing is a therapeutic target for analgesia |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2014-11-01 |
description |
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. |
topic |
Vascular endothelial growth factor A Alternative mRNA splicing Neuropathy Nociceptors |
url |
http://www.sciencedirect.com/science/article/pii/S0969996114002435 |
work_keys_str_mv |
AT rphulse regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT nbeazleylong regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT jhua regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT hkennedy regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT jprager regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT hbevan regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT yqiu regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT esfernandes regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT mvgammons regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT kballmerhofer regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT acgittenbergerdegroot regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT ajchurchill regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT sjharper regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT sdbrain regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT dobates regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia AT lfdonaldson regulationofalternativevegfamrnasplicingisatherapeutictargetforanalgesia |
_version_ |
1724208280467668992 |