Vascular Endothelial Growth Factor A Signaling Promotes Spinal Central Sensitization and Pain-related Behaviors in Female Rats with Bone Cancer
Vascular Endothelial Growth Factor A Signaling Promotes Spinal Central Sensitization and Pain-related Behaviors in Female Rats with Bone Cancer
复制标题
血管内皮生长因子 A 信号传导促进患有骨癌的雌性大鼠的脊髓中枢敏化和疼痛相关行为
DOI：
10.1097/aln.0000000000002916
复制
发表时间：
2019-11-01
期刊：
影响因子：
8.8
通讯作者：
Wang, Yan-Qing
中科院分区：
文献类型：
--
作者：
Hu, Xue-Ming;Yang, Wei;Wang, Yan-Qing
背景：癌痛是影响患者生活质量的常见临床症状。血管内皮生长因子A在肿瘤血管生成中的作用已被充分研究，并被认为是抗癌治疗的治疗靶点。本研究测试的假设，血管内皮生长因子A和血管内皮生长因子受体2有助于骨癌疼痛的调节与脊髓中枢sensitization.Methods：本研究进行了雌性大鼠使用转移性乳腺癌骨痛模型。伤害性行为通过机械异常性疼痛、热痛觉过敏、自发性疼痛和CatWalk步态分析进行评估。通过实时定量聚合酶链反应、蛋白质印迹和免疫荧光分析来测量表达水平。全细胞膜片钳记录检测兴奋性突触传递。主要观察结果是脊髓血管内皮生长因子A/血管内皮生长因子受体2信号转导的药物干预对骨癌疼痛行为的影响。结果：荷瘤大鼠脊髓血管内皮生长因子A和血管内皮生长因子受体2的mRNA和蛋白表达上调。脊髓阻断血管内皮生长因子A或血管内皮生长因子受体2可显著减轻肿瘤诱导的机械性异常性疼痛（平均SD：血管内皮生长因子A，7.6 +/- 2.6 g vs. 5.3 +/- 3.3 g;血管内皮生长因子受体2，7.8 +/- 3.0 g vs. 5.2 +/- 3.4 g; n = 6; P < 0.0001）和热痛觉过敏（平均值+/- SD：血管内皮生长因子A，9.0 +/- 2.4 s vs. 7.4 +/- 2.7 s;血管内皮生长因子受体2，9.3 +/- 2.5 s vs. 7.5 +/- 3.1 s; n = 6; P < 0.0001），以及自发性疼痛和异常步态。外源性血管内皮生长因子A以血管内皮生长因子受体2依赖的方式增强兴奋性突触传递，脊髓注射外源性血管内皮生长因子A足以通过血管内皮生长因子受体2介导的蛋白激酶C和Src家族激酶激活引起疼痛超敏反应。此外，脊髓阻断血管内皮生长因子A/血管内皮生长因子受体2通路抑制蛋白激酶C介导的N-甲基-d-天冬氨酸受体活化和Src家族激酶介导的促炎细胞因子产生。血管内皮生长因子A/血管内皮生长因子受体2通过激活神经元蛋白激酶C和小胶质细胞Src参与中枢致敏和骨癌疼痛脊髓中的家族激酶通路。
Background: Cancer pain is a pervasive clinical symptom impairing life quality. Vascular endothelial growth factor A has been well studied in tumor angiogenesis and is recognized as a therapeutic target for anti-cancer treatment. This study tested the hypothesis that vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 contribute to bone cancer pain regulation associated with spinal central sensitization.Methods: This study was performed on female rats using a metastatic breast cancer bone pain model. Nociceptive behaviors were evaluated by mechanical allodynia, thermal hyperalgesia, spontaneous pain, and CatWalk gait analysis. Expression levels were measured by real-time quantitative polymerase chain reaction, western blot, and immunofluorescence analysis. Excitatory synaptic transmission was detected by whole-cell patch-clamp recordings. The primary outcome was the effect of pharmacologic intervention of spinal vascular endothelial growth factor A/vascular endothelial growth factor receptor 2-signaling on bone cancer pain behaviors.Results: The mRNA and protein expression of vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 were upregulated in tumor-bearing rats. Spinal blocking vascular endothelial growth factor A or vascular endothelial growth factor receptor 2 significantly attenuated tumor-induced mechanical allodynia (mean SD: vascular endothelial growth factor A, 7.6 +/- 2.6 g vs. 5.3 +/- 3.3 g; vascular endothelial growth factor receptor 2, 7.8 +/- 3.0 g vs. 5.2 +/- 3.4 g; n = 6; P < 0.0001) and thermal hyperalgesia (mean +/- SD: vascular endothelial growth factor A, 9.0 +/- 2.4 s vs. 7.4 +/- 2.7 s; vascular endothelial growth factor receptor 2, 9.3 +/- 2.5 s vs. 7.5 +/- 3.1 s; n = 6; P < 0.0001), as well as spontaneous pain and abnormal gaits. Exogenous vascular endothelial growth factor A enhanced excitatory synaptic transmission in a vascular endothelial growth factor receptor 2-dependent manner, and spinal injection of exogenous vascular endothelial growth factor A was sufficient to cause pain hypersensitivity via vascular endothelial growth factor receptor 2-mediated activation of protein kinase C and Src family kinase in naive rats. Moreover, spinal blocking vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 pathways suppressed protein kinase C-mediated N-methyl-d-aspartate receptor activation and Src family kinase-mediated proinflammatory cytokine production.Conclusions: Vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 contributes to central sensitization and bone cancer pain via activation of neuronal protein kinase C and microglial Src family kinase pathways in the spinal cord.