Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China.
Reprod Biol Endocrinol. 2022 Jun 4;20(1):85. doi: 10.1186/s12958-022-00955-w.
Women with endometriosis have been shown to have a reduced vagal tone as compared with controls and vagotomy promoted while vagus nerve stimulation (VNS) decelerated the progression of endometriosis in mice. Extensive research also has shown that the activation of the cholinergic anti-inflammatory pathway by VNS activates α7 nicotinic acetylcholine receptor (α7nAChR), potently reducing inflammation. Yet whether α7nAChR plays any role in endometriosis is unknown. We evaluated its expression in normal endometrium, ovarian and deep endometriotic lesions, and evaluated its role in the development of endometriosis.
Immunohistochemistry analyses of α7nAChR in endometriotic lesions as well as control endometrium, and quantification of tissue fibrosis by Masson trichrome staining were performed. Mouse experiments were conducted to evaluate the impact of α7nAChR activation or suppression on lesional progression and possible therapeutic effect. Finally, in vitro experiments were conducted to evaluate the effect of activation of α7nAChR on epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM) and fibrogenesis in an endometriotic epithelial cell line and primary endometriotic stromal cells derived from ovarian endometrioma tissue samples.
Immunostaining of α7nAChR was significantly reduced in human endometriotic epithelial cells as compared with their counterpart in normal endometrium. Lesional α7nAChR staining levels correlated negatively with lesional fibrosis and the severity of dysmenorrhea. The α7nAChR agonist significantly impeded the development of endometriotic lesions in mouse models possibly through hindrance of EMT and FMT. It also demonstrated therapeutic effects in mice with induced deep endometriosis. Treatment of endometriotic epithelial and stromal cells with an α7nAChR agonist significantly abrogated platelet-induced EMT, FMT and SMM, and suppressed cellular contractility and collagen production.
α7nAChR is suppressed in endometriotic lesions, and its activation by pharmacological means can impede EMT, FMT, SMM, and fibrogenesis of endometriotic lesions. As such, α7nAChR can be rightfully viewed as a potential target for therapeutic invention.
Not applicable.
与对照组相比，子宫内膜异位症患者的迷走神经张力降低，而迷走神经切断术促进、迷走神经刺激（VNS）则减缓了小鼠子宫内膜异位症的进展。大量研究还表明，VNS 激活胆碱能抗炎途径可激活α7 烟碱型乙酰胆碱受体（α7nAChR），强力抑制炎症。然而，α7nAChR 是否在子宫内膜异位症中发挥作用尚不清楚。我们评估了它在正常子宫内膜、卵巢和深部子宫内膜异位症病变中的表达，并评估了它在子宫内膜异位症发展中的作用。
对子宫内膜异位症病变以及对照子宫内膜中的α7nAChR 进行免疫组织化学分析，并通过 Masson 三色染色定量组织纤维化。进行了小鼠实验以评估α7nAChR 激活或抑制对病变进展和可能的治疗效果的影响。最后，进行了体外实验以评估激活α7nAChR 对子宫内膜上皮细胞系和源自卵巢子宫内膜异位瘤组织样本的原代子宫内膜间质细胞中的上皮-间充质转化（EMT）、成纤维细胞-肌成纤维细胞转分化（FMT）、平滑肌化生（SMM）和纤维发生的影响。
与正常子宫内膜中的对应物相比，人子宫内膜异位症上皮细胞中的α7nAChR 免疫染色明显减少。病变中α7nAChR 的染色水平与病变纤维化和痛经严重程度呈负相关。α7nAChR 激动剂显著阻碍了小鼠模型中子宫内膜异位症病变的发展，可能是通过阻碍 EMT 和 FMT。它还在诱导的深部子宫内膜异位症小鼠中显示出治疗效果。用 α7nAChR 激动剂处理子宫内膜异位症上皮细胞和基质细胞可显著阻断血小板诱导的 EMT、FMT 和 SMM，并抑制细胞收缩性和胶原产生。
α7nAChR 在子宫内膜异位症病变中受到抑制，其通过药理学手段激活可阻碍子宫内膜异位症病变的 EMT、FMT、SMM 和纤维化。因此，α7nAChR 可以被视为治疗发明的潜在靶点。
不适用。
