Cancer Biology, Division of Cancer and Stem Cells, School of Medicine University of Nottingham, Nottingham, NG7 2UH, UK.
Institute of Ophthalmology, 11-43 Bath St, London, EC1V 9EL, UK.
J Physiol. 2018 Aug;596(16):3675-3693. doi: 10.1113/JP275067. Epub 2018 Jul 11.
Diabetes is thought to induce neuropathic pain through activation of dorsal horn sensory neurons in the spinal cord. Here we explore the impact of hyperglycaemia on the blood supply supporting the spinal cord and chronic pain development. In streptozotocin-induced diabetic rats, neuropathic pain is accompanied by a decline in microvascular integrity in the dorsal horn. Hyperglycaemia-induced degeneration of the endothelium in the dorsal horn was associated with a loss in vascular endothelial growth factor (VEGF)-A b expression. VEGF-A b treatment prevented diabetic neuropathic pain and degeneration of the endothelium in the spinal cord. Using an endothelial-specific VEGFR2 knockout transgenic mouse model, the loss of endothelial VEGFR2 signalling led to a decline in vascular integrity in the dorsal horn and the development of hyperalgesia in VEGFR2 knockout mice. This highlights that vascular degeneration in the spinal cord could be a previously unidentified factor in the development of diabetic neuropathic pain.
Abnormalities of neurovascular interactions within the CNS 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 vascular endothelial growth factor (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-A b 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, and there was a concurrent reduction of VEGF-A b expression. In diabetic animals, VEGF-A b treatment (biweekly i.p., 20 ng g ) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes-induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreER -vegfr2 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.
糖尿病被认为通过激活脊髓背角感觉神经元而引起神经性疼痛。在这里，我们探讨了高血糖对支持脊髓和慢性疼痛发展的血液供应的影响。在链脲佐菌素诱导的糖尿病大鼠中，神经性疼痛伴随着背角微血管完整性的下降。高血糖诱导的背角内皮变性与血管内皮生长因子（VEGF）-A b 表达的丧失有关。VEGF-A b 治疗可预防糖尿病性神经病理性疼痛和脊髓内皮变性。使用内皮特异性 VEGFR2 敲除转基因小鼠模型，内皮 VEGFR2 信号的丧失导致背角血管完整性下降和 VEGFR2 敲除小鼠痛觉过敏的发展。这突出表明，脊髓内的血管变性可能是糖尿病性神经病理性疼痛发展中的一个以前未被识别的因素。
糖尿病患者中枢神经系统内神经血管相互作用的异常与许多神经疾病状态的发生有关。然而，尽管糖尿病中经常出现神经性疼痛，但迄今为止，尚未研究脊髓内神经血管网络与伤害感受调节之间的联系。我们假设，由于血管内皮生长因子（VEGF）-A/VEGFR2 信号的抑制，高血糖诱导的脊髓内皮变性会引起糖尿病性神经病理性疼痛。在化学诱导的 1 型糖尿病模型（链脲佐菌素诱导，胰岛素补充；载体或 VEGF-A b 治疗）和可诱导的内皮 VEGFR2 敲低（他莫昔芬诱导）中，研究了伤害感受疼痛行为。糖尿病动物出现机械性痛觉过敏和热痛觉过敏。与年龄匹配的对照组相比，这与糖尿病动物腰椎脊髓中血管数量减少和伊文思蓝外渗减少有关。与对照组相比，糖尿病组脊髓中的内皮标志物紧密连接蛋白、CD31 和 VE-钙粘蛋白下调，同时 VEGF-A b 表达减少。在糖尿病动物中，VEGF-A b 治疗（每周两次腹腔注射，20ng g ）恢复了正常的伊文思蓝外渗，并防止了血管变性、糖尿病诱导的中枢神经元激活和神经病理性疼痛。可诱导的 VEGFR2 敲低（他莫昔芬处理 Tie2CreER -vegfr2 小鼠）导致腰椎脊髓血管网络体积减少和热痛觉过敏的发展。这些发现表明，高血糖导致 VEGF-A/VEGFR2 信号级联反应减少，导致脊髓内皮功能障碍，这可能是糖尿病性神经病理性疼痛的一个未被发现的致病因素。
