Vascular endothelial growth factor-A is involved in intramuscular carrageenan-induced cutaneous mechanical hyperalgesia through the vascular endothelial growth factor-A receptor 1 and transient receptor potential vanilloid 1 pathways
Vascular endothelial growth factor-A is involved in intramuscular carrageenan-induced cutaneous mechanical hyperalgesia through the vascular endothelial growth factor-A receptor 1 and transient receptor potential vanilloid 1 pathways
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血管内皮生长因子-A 通过血管内皮生长因子-A 受体 1 和瞬时受体电位香草酸 1 途径参与肌内角叉菜胶诱导的皮肤机械痛觉过敏
DOI：
10.1097/wnr.0000000000001885
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发表时间：
2023
期刊：
影响因子：
1.7
通讯作者：
Ugawa Shinya
中科院分区：
文献类型：
--
作者：
Ueda Takashi;Watanabe Masaya;Miwa Youko;Shibata Yasuhiro;Kumamoto Natsuko;Ugawa Shinya
目的血管内皮生长因子-A（VEGF-A）在肿瘤和慢性疼痛的血管生成和疼痛超敏反应中起主导作用。它不仅由缺血性条件诱导，而且还与促痛细胞因子高度相关，这两者在炎性肌肉疼痛中都很突出。然而，VEGF-A参与肌肉疼痛的分子基础仍然未知。MethodsIn本研究，我们进行了行为学和药理学分析，以确定VEGF-A在炎症性肌肉疼痛的发展和相关的信号转导通路中的可能参与。注射部位周围组织中VEGF-A基因表达增加。肌肉注射重组VEGF-A 165在同侧诱导皮肤机械性痛觉过敏在急性和亚急性阶段。在同侧应用特异性VEGFR 1抗体显著降低了角叉菜胶或VEGF-A165注射诱导的机械性痛觉过敏，而VEGFR 2中和抗体和VEGFR 2拮抗剂均显示出有限的作用。局部预注射辣椒平，一种瞬时受体电位香草酸1（TRPV 1）拮抗剂，也抑制VEGF-A 165诱导的痛觉过敏。最后，肌内VEGF-A 165诱导的机械性痛觉过敏没有发现在TRPV 1基因敲除小鼠在亚急性phase.ConclusionsThese研究结果表明，炎症刺激增加间质VEGF-A 165，这反过来又诱导皮肤机械性疼痛通过VEGFR 1介导的TRPV 1伤害性通路在炎症性肌肉疼痛。VEGFR 1可能成为炎症诱导的肌肉疼痛的一个新的治疗靶点。
ObjectivesVascular endothelial growth factor-A (VEGF-A) plays a leading role in angiogenesis and pain hypersensitivity in cancer and chronic pain. It is not only induced by ischemic conditions but is also highly correlated with proalgesic cytokines, both of which are prominent in inflammatory muscle pain. However, the molecular basis of the involvement of VEGF-A in muscle pain remains unknown.MethodsIn the present study, we performed behavioral and pharmacological analyses to determine the possible involvement of VEGF-A in the development of inflammatory muscle pain and the associated signal transduction pathway.ResultsUnilateral intramuscular injection of carrageenan, a classical model of inflammatory muscle pain, increased VEGF-A gene expression in the tissues surrounding the injection site. Intramuscular administration of recombinant VEGF-A 165 on the same side induced cutaneous mechanical hyperalgesia during the acute and subacute phases. The application of a specific VEGFR1 antibody on the same side significantly reduced the mechanical hyperalgesia induced by carrageenan or VEGF-A 165 injection, whereas both a VEGFR2-neutralizing antibody and a VEGFR2 antagonist showed limited effects. Local preinjection of capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist, also inhibited VEGF-A 165-induced hyperalgesia. Finally, intramuscular VEGF-A 165-induced mechanical hyperalgesia was not found in TRPV1 knockout mice during the subacute phase.ConclusionsThese findings suggest that inflammatory stimuli increase interstitial VEGF-A 165, which in turn induces cutaneous mechanical pain via the VEGFR1-mediated TRPV1 nociceptive pathway during inflammatory muscle pain. VEGFR1 could be a novel therapeutic target for inflammation-induced muscle pain.