Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain
Abnormalities of neurovascular interactions within the central nervous system of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investig...
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| Format: | Article |
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Wiley
2018
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| Online Access: | https://eprints.nottingham.ac.uk/51715/ |
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| author | Ved, Nikita Da Vitoria Lobo, M.E. Bestall, Samuel M. Vidueira, C.L. Beazley-Long, Nicholas Ballmer-Hofer, Kurt Hirashima, Masanori Bates, David O. Donaldson, Lucy F. Hulse, Richard P. |
| author_facet | Ved, Nikita Da Vitoria Lobo, M.E. Bestall, Samuel M. Vidueira, C.L. Beazley-Long, Nicholas Ballmer-Hofer, Kurt Hirashima, Masanori Bates, David O. Donaldson, Lucy F. Hulse, Richard P. |
| author_sort | Ved, Nikita |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Abnormalities of neurovascular interactions within the central nervous system of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investigated despite neuropathic pain being common in diabetes. We hypothesised that hyperglycaemia-induced endothelial degeneration in the spinal cord, due to suppression of VEGF-A/VEGFR2 signalling, induces diabetic neuropathic pain. Nociceptive pain behaviour was investigated in a chemically induced model of type 1 diabetes (streptozotocin induced, insulin supplemented; either vehicle or VEGF-A165b treated) and an inducible endothelial knockdown of VEGFR2 (tamoxifen induced). Diabetic animals developed mechanical allodynia and heat hyperalgesia. This was associated with a reduction in the number of blood vessels and reduction in Evans blue extravasation in the lumbar spinal cord of diabetic animals versus age-matched controls. Endothelial markers occludin, CD31 and VE-cadherin were downregulated in the spinal cord of the diabetic group versus controls, as well as a concurrent reduction of VEGF-A165b expression. In diabetic animals, VEGF-A165b treatment (biweekly intraperitoneal, 20ng/g) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes-induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreERT2-vegfr2flfl mice) led to a reduction in blood vessel network volume in the lumbar spinal cord and development of heat hyperalgesia. These findings indicate that hyperglycaemia leads to a reduction in the VEGF-A/VEGFR2 signalling cascade resulting in endothelial dysfunction in the spinal cord, which could be an undiscovered contributing factor to diabetic neuropathic pain. |
| first_indexed | 2025-11-14T20:21:40Z |
| format | Article |
| id | nottingham-51715 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:21:40Z |
| publishDate | 2018 |
| publisher | Wiley |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-517152020-05-04T19:36:59Z https://eprints.nottingham.ac.uk/51715/ Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain Ved, Nikita Da Vitoria Lobo, M.E. Bestall, Samuel M. Vidueira, C.L. Beazley-Long, Nicholas Ballmer-Hofer, Kurt Hirashima, Masanori Bates, David O. Donaldson, Lucy F. Hulse, Richard P. Abnormalities of neurovascular interactions within the central nervous system of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investigated despite neuropathic pain being common in diabetes. We hypothesised that hyperglycaemia-induced endothelial degeneration in the spinal cord, due to suppression of VEGF-A/VEGFR2 signalling, induces diabetic neuropathic pain. Nociceptive pain behaviour was investigated in a chemically induced model of type 1 diabetes (streptozotocin induced, insulin supplemented; either vehicle or VEGF-A165b treated) and an inducible endothelial knockdown of VEGFR2 (tamoxifen induced). Diabetic animals developed mechanical allodynia and heat hyperalgesia. This was associated with a reduction in the number of blood vessels and reduction in Evans blue extravasation in the lumbar spinal cord of diabetic animals versus age-matched controls. Endothelial markers occludin, CD31 and VE-cadherin were downregulated in the spinal cord of the diabetic group versus controls, as well as a concurrent reduction of VEGF-A165b expression. In diabetic animals, VEGF-A165b treatment (biweekly intraperitoneal, 20ng/g) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes-induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreERT2-vegfr2flfl mice) led to a reduction in blood vessel network volume in the lumbar spinal cord and development of heat hyperalgesia. These findings indicate that hyperglycaemia leads to a reduction in the VEGF-A/VEGFR2 signalling cascade resulting in endothelial dysfunction in the spinal cord, which could be an undiscovered contributing factor to diabetic neuropathic pain. Wiley 2018-08-15 Article PeerReviewed Ved, Nikita, Da Vitoria Lobo, M.E., Bestall, Samuel M., Vidueira, C.L., Beazley-Long, Nicholas, Ballmer-Hofer, Kurt, Hirashima, Masanori, Bates, David O., Donaldson, Lucy F. and Hulse, Richard P. (2018) Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain. Journal of Physiology, 596 (16). pp. 3675-3693. ISSN 1469-7793 Pain; Diabetes; Endothelial https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP275067 doi:10.1113/JP275067 doi:10.1113/JP275067 |
| spellingShingle | Pain; Diabetes; Endothelial Ved, Nikita Da Vitoria Lobo, M.E. Bestall, Samuel M. Vidueira, C.L. Beazley-Long, Nicholas Ballmer-Hofer, Kurt Hirashima, Masanori Bates, David O. Donaldson, Lucy F. Hulse, Richard P. Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain |
| title | Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain |
| title_full | Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain |
| title_fullStr | Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain |
| title_full_unstemmed | Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain |
| title_short | Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain |
| title_sort | diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain |
| topic | Pain; Diabetes; Endothelial |
| url | https://eprints.nottingham.ac.uk/51715/ https://eprints.nottingham.ac.uk/51715/ https://eprints.nottingham.ac.uk/51715/ |