Diabetes-induced microvascular complications at the level of the spinal cord; a contributing factor in diabetic neuropathic pain

Ved, N., Da Vitoria Lobo, M.E., Bestall, S.M., Vidueira, C.L., Beazley-Long, N., Ballmer-Hofer, K., Hirashima, M., Bates, D.O., Donaldson, L.F. and Hulse, R.P. ORCID: 0000-0002-5193-9822, 2018. Diabetes-induced microvascular complications at the level of the spinal cord; a contributing factor in diabetic neuropathic pain. The Journal of Physiology. ISSN 0022-3751

[img]
Preview
Text
11142_Hulse.pdf - Post-print

Download (2MB) | Preview

Abstract

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.

Item Type: Journal article
Alternative Title: Diabetes-induced microvascular degeneration and neuropathic pain [running title]
Publication Title: The Journal of Physiology
Creators: Ved, N., Da Vitoria Lobo, M.E., Bestall, S.M., Vidueira, C.L., Beazley-Long, N., Ballmer-Hofer, K., Hirashima, M., Bates, D.O., Donaldson, L.F. and Hulse, R.P.
Publisher: Wiley-Blackwell
Date: 17 May 2018
ISSN: 0022-3751
Identifiers:
NumberType
10.1113/JP275067DOI
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 21 May 2018 10:33
Last Modified: 21 May 2018 10:33
URI: http://irep.ntu.ac.uk/id/eprint/33627

Actions (login required)

Edit View Edit View

Views

Views per month over past year

Downloads

Downloads per month over past year