VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis.
VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis.
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DOI：
10.1016/j.bbi.2018.03.012
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Donaldson LF
中科院分区：
文献类型：
--
作者：
Beazley-Long N;Hodge D;Ashby WR;Bestall SM;Almahasneh F;Durrant AM;Benest AV;Blackley Z;Ballmer-Hofer K;Hirashima M;Hulse RP;Bates DO;Donaldson LF
靶向VEGFR 2预防炎症性关节炎模型中的继发性异常性疼痛。抗VEGFR 2减少背角中的血管ICAM-1和小胶质细胞。抗VEGFR 2抑制单核细胞与脑内皮细胞的附着。我们提出了一种新的神经胶质血管免疫机制，促进疼痛。治疗性抗VEGFR 2可以减轻炎症性关节炎的慢性疼痛。慢性疼痛可以在炎症性关节炎等疾病的反应中发展。尽管有证据表明小胶质细胞和星形胶质细胞的作用，但人类慢性疼痛发展和维持的中枢机制尚未得到很好的阐明。然而，在临床前疼痛模型中，包括炎性关节炎模型，有大量证据表明CNS内病理性神经胶质反应性的作用。在疼痛性炎性关节炎大鼠的脊髓背角中，我们发现与血管相关的CD 11b+小胶质细胞样细胞和GFAP+星形胶质细胞显著增加，并且表达粘附分子ICAM-1的活化血管的数量显著增加，表明潜在的胶质血管活化。在关节炎大鼠中使用靶向VEGFR 2的药物干预来抑制内皮细胞活化，背角ICAM-1+血管的数量、CD 11b+小胶质细胞和继发性机械异常性疼痛的发展（中枢致敏的指标）都被阻止。通过诱导型Tie 2特异性VEGFR 2敲除靶向内皮VEGFR 2也防止了小鼠中的继发性异常性疼痛和响应于炎性关节炎的背角中的神经胶质血管活化。在体外抑制VEGFR 2可显著阻断炎症介质TNF-α和VEGF-A165 a刺激时ICAM-1依赖性单核细胞与脑微血管内皮细胞的粘附。总之，我们的研究结果表明，一种新的VEGFR 2介导的脊髓胶质血管机制可能会促进外周CD 11b+循环细胞迁移到中枢神经系统实质，并有助于炎症性关节炎慢性疼痛的发展。我们假设，防止这种胶质血管激活和循环细胞移位到脊髓可能是一种新的治疗策略，由类风湿性关节炎引起的疼痛。
Targeting VEGFR2 prevents secondary allodynia in inflammatory arthritis models. Anti-VEGFR2 reduces vascular ICAM-1 and microglia in the dorsal horn. Anti-VEGFR2 inhibits monocyte attachment to brain endothelial cells. We propose a novel glio-vascular-immune mechanism that promotes pain. Therapeutic anti-VEGFR2 may lessen chronic pain in inflammatory arthritis. Chronic pain can develop in response to conditions such as inflammatory arthritis. The central mechanisms underlying the development and maintenance of chronic pain in humans are not well elucidated although there is evidence for a role of microglia and astrocytes. However in pre-clinical models of pain, including models of inflammatory arthritis, there is a wealth of evidence indicating roles for pathological glial reactivity within the CNS. In the spinal dorsal horn of rats with painful inflammatory arthritis we found both a significant increase in CD11b+ microglia-like cells and GFAP+ astrocytes associated with blood vessels, and the number of activated blood vessels expressing the adhesion molecule ICAM-1, indicating potential glio-vascular activation. Using pharmacological interventions targeting VEGFR2 in arthritic rats, to inhibit endothelial cell activation, the number of dorsal horn ICAM-1+ blood vessels, CD11b+ microglia and the development of secondary mechanical allodynia, an indicator of central sensitization, were all prevented. Targeting endothelial VEGFR2 by inducible Tie2-specific VEGFR2 knock-out also prevented secondary allodynia in mice and glio-vascular activation in the dorsal horn in response to inflammatory arthritis. Inhibition of VEGFR2 in vitro significantly blocked ICAM-1-dependent monocyte adhesion to brain microvascular endothelial cells, when stimulated with inflammatory mediators TNF-α and VEGF-A165a. Taken together our findings suggest that a novel VEGFR2-mediated spinal cord glio-vascular mechanism may promote peripheral CD11b+ circulating cell transmigration into the CNS parenchyma and contribute to the development of chronic pain in inflammatory arthritis. We hypothesise that preventing this glio-vascular activation and circulating cell translocation into the spinal cord could be a new therapeutic strategy for pain caused by rheumatoid arthritis.
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