目的 基于缺氧诱导因子 1A（HIF1A）/zeste 增强子同源物 2（EZH2）/炭疽热毒素受体 2（ANTXR2）信号通 路探讨罗氏内异方（又名益母调经化瘀合剂）对子宫内膜异位症（EMs）大鼠在位子宫内膜增殖及血管生成的干预 作用及机制。方法 将 SD 大鼠随机分为伪手术组、模型组、达那唑组（4.2 g·kg-1）及罗氏内异方低、高剂量组 （15.74、31.48 g·kg-1），每组 8 只。采用自体子宫内膜移植联合多因素干预法复制气滞血瘀型 EMs 病证结合大 鼠模型。灌胃给药，每天 1 次，连续 28 d。采用 HE 染色法观察子宫内膜组织病理变化；免疫组化法检测子宫 内膜组织中增殖细胞蛋白 67（Ki67）和血小板内皮细胞黏附分子 1（CD31）蛋白表达水平；qRT-PCR 及 Western Blot 法检测子宫内膜组织中 HIF1A、EZH2、ANTXR2 mRNA 及蛋白表达水平；Western Blot 法检测子 宫内膜组织中 Yes 关联蛋白 1 （YAP1）、吞噬细胞糖蛋白 1 （CD44）、β-连环蛋白 （β-catenin） 蛋白表达水平。 结果 与伪手术组相比，模型组大鼠在位子宫内膜组织上皮细胞增厚，间质细胞排列紊乱，炎性细胞增多；子 宫内膜组织中 Ki67、CD31 的表达水平均显著升高（P＜0.01），HIF1A、ANTXR2 mRNA 及蛋白表达水平均显著 升高（P＜0.01），而 EZH2 mRNA 及蛋白表达水平显著下降（P＜0.01），YAP1、CD44 及 β-catenin 蛋白表达水 平均显著升高（P＜0.01）。与模型组比较，各给药组大鼠在位子宫内膜组织上皮层变薄，间质部细胞紊乱和炎 症浸润均有改善，子宫内膜组织中 Ki67、CD31 的表达水平均显著降低（P＜0.01）；达那唑组与罗氏内异方高 剂量组大鼠子宫内膜组织中 HIF1A、ANTXR2 mRNA 及蛋白表达水平均明显降低（P＜0.05，P＜0.01），EZH2 mRNA 及蛋白表达水平明显升高（P＜0.05，P＜0.01）；各给药组大鼠子宫内膜组织中 YAP1、CD44 及 β -catenin 蛋白表达水平均显著降低（P＜0.05，P＜0.01）。结论 罗氏内异方可通过抑制在位子宫内膜细胞的增 殖及血管生成能力来发挥治疗 EMs 的作用，其机制可能与抑制 HIF1A/EZH2/ANTXR2 信号通路有关。

Objective To investigate the intervention effect and mechanism of LUO’s Neiyi Prescription on the proliferation and angiogenesis of eutopic endometrium in rats with endometriosis （EMs） based on hypoxia-inducible factor 1A （HIF1A）/enhancer of zeste homolog 2 （EZH2）/anthrax toxin receptor 2 （ANTXR2）signaling pathway.Methods SD rats were randomly divided into sham operation group，model group，Danazol group （4. 2 g·kg-1）， low-dose LUO’s Neiyi Prescription group and high-dose LUO’s Neiyi Prescription group （15. 74，31.48 g·kg-1）， eight rats in each group. The rat model of EMs with qi stagnation and blood stasis syndrome was constructed by autologous endometrial transplantation combined with multi-factor intervention. Intragastric administration was given once a day for 28 consecutive days. The pathological changes of endometrial tissue were observed by HE staining. The expression levels of proliferating cell protein 67（Ki67）and platelet endothelial cell adhesion molecule 1（CD31） in endometrial tissue were detected by immunohistochemistry. The mRNA and protein expression levels of HIF1A， EZH2 and ANTXR2 in endometrial tissues were detected by qRT-PCR and Western Blot. The expression levels of YAP1，CD44 and β-catenin in endometrial tissues were detected by Western Blot. Results Compared with the sham operation group，the epithelial cells of the eutopic endometrium of the model group were thickened，the interstitial cells were arranged disorderly，and the inflammatory cells increased. The expression levels of Ki67 and CD31 in endometrial tissues were significantly increased （P＜0.01），the mRNA and protein expression levels of HIF1A and ANTXR2 were significantly increased （P＜0.01）， while the mRNA and protein expression levels of EZH2 were significantly decreased （P＜0.01）， and the protein expression levels of YAP1， CD44 and β -catenin were significantly increased （P＜0.01）. Compared with the model group，the epithelial layer of the eutopic endometrial tissue of the rats in each administration group became thinner，the interstitial disorder and inflammatory infiltration were improved，and the levels of Ki67 and CD31 in the eutopic endometrial tissue were significantly decreased （P＜ 0.01）. The mRNA and protein expression levels of HIF1A and ANTXR2 in the endometrium of rats in the Danazol group and the high-dose LUO’s Neiyi Prescription group were significantly decreased （P＜0.05，P＜0.01），and the mRNA and protein expression levels of EZH2 were significantly increased （P＜0.05， P＜0.01）. The protein expression levels of YAP1， CD44 and β -catenin in endometrial tissue of rats in each administration group were significantly decreased （P＜0.05，P＜0.01）. Conclusion LUO’s Neiyi Prescription can play a role in the treatment of EMs by inhibiting the proliferation and angiogenesis of eutopic endometrial cells， and its mechanism may be related to the inhibition of HIF1A/EZH2/ANTXR2 signaling pathway.

R285.5

国家自然科学基金项目（82305288，82074481）；国家中医药传承创新中心科研专项（2022QN22）；邓高丕名中医传承工作室（粤中医办 函[2019]5号）。