实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (2): 130-146.DOI: 10.12300/j.issn.1674-5817.2024.132
连辉1, 姜艳玲1, 刘佳1, 张玉立2, 谢伟2, 薛晓鸥2, 李健1(
)(
)
收稿日期:2024-09-05
修回日期:2025-01-07
出版日期:2025-04-25
发布日期:2025-04-25
通讯作者:
李健（1970—），男，博士，教授，博士生导师，主要从事中西医结合防治炎症相关疾病的机制研究。E-mail：lijian@bucm.edu.cn。ORCID： 0000-0002-8864-0621作者简介:连 辉（1996—），男，硕士研究生，研究方向：中医药防治慢性非可控炎症。E-mail：20210931078@bucm.edu.cn
基金资助:
LIAN Hui1, JIANG Yanling1, LIU Jia1, ZHANG Yuli2, XIE Wei2, XUE Xiaoou2, LI Jian1()()
Received:2024-09-05
Revised:2025-01-07
Published:2025-04-25
Online:2025-04-25
Contact:
LI Jian (ORCID: 0000-0002-8864-0621), E-mail: lijian@bucm.edu.cn摘要：
目的 通过模拟排卵功能障碍型异常子宫出血（abnormal uterine bleeding-ovulatory dysfunction，AUB-O）病因，建立异常子宫出血大鼠模型，为异常子宫出血病理机制研究及治疗药物开发提供可靠的模型支持。 方法 将24只成年（10周龄）雌性SD大鼠适应性饲养后，随机分为正常对照组（6只）和模型组（18只）。正常对照组大鼠在屏障环境中正常饲养；模型组大鼠在屏障环境中经背侧入路行双侧卵巢切除术，休养1周后开始造模用药。模型组造模第1 ~ 3天每日每只大鼠背部皮下注射雌二醇0.5 mg，第4 ~ 7天每日皮下注射孕酮5.0 mg；同时于第6天经背侧相同手术切口向双侧子宫腔各注射0.5 mL大豆油，于第8天行米非司酮（10 mg/kg）灌胃，造模期间持续观察大鼠所处动情周期的阶段及其变化趋势。造模后48 h内观察并记录大鼠子宫出血情况，米非司酮灌胃后0、12、24、36、48 h模型组动态收集血清和子宫组织样本，正常对照组在36 h同时取材。取材后分别进行HE染色、血清性激素ELISA测定、免疫组织化学检测、TUNEL凋亡染色、蛋白质印迹检测、转录组学测序和生物信息学分析，对异常子宫出血大鼠模型进行综合评价。 结果 异常子宫出血大鼠表现为子宫出血，内膜剥脱损伤、复旧不全，内膜炎性细胞浸润、凋亡增强，间质、腺体和血管结构破坏。与正常对照组相比，异常子宫出血大鼠的血清卵泡刺激素、雌二醇和促黄体生成素水平明显升高（P<0.05）；子宫内膜血管密度明显降低（P<0.05）；血管内皮生长因子在子宫内膜剥脱处表达定性观察到明显增强，而在间质血管周围表达显著下降（P<0.01）；基质金属蛋白酶-9在内膜损伤部位表达定性观察到明显增强，而在未剥脱间质和腺体处表达显著降低（P<0.01）；子宫内膜间质细胞凋亡显著增强（P<0.01）；成纤维细胞生长因子2和内皮素-1在子宫组织中的表达水平均明显下降（P<0.05）。比较异常子宫出血大鼠与正常大鼠子宫组织的转录组测序结果，共筛选到4 723个差异表达基因，其中表达上调基因为2 191个，表达下调基因为2 532个；KEGG富集分析显示，差异基因显著富集在炎症、免疫凋亡、细胞信号转导、增殖分化和肌肉收缩等相关通路。 结论 采用雌激素、孕激素和米非司酮序贯给药模拟AUB-O病因的方法，可成功建立异常子宫出血大鼠模型。该模型的子宫内膜损伤与炎症和凋亡相关，病理表现受血管收缩和内膜再生能力异常影响。该大鼠模型具有与临床非结构性病因异常子宫出血相近的病理特征，可以作为研究病理机制和治疗方法的有效模型。
中图分类号:
连辉,姜艳玲,刘佳,等. 异常子宫出血大鼠模型的构建与评价[J]. 实验动物与比较医学, 2025, 45(2): 130-146. DOI: 10.12300/j.issn.1674-5817.2024.132.
LIAN Hui,JIANG Yanling,LIU Jia,et al. Construction and Evaluation of a Rat Model of Abnormal Uterine Bleeding[J]. Laboratory Animal and Comparative Medicine, 2025, 45(2): 130-146. DOI: 10.12300/j.issn.1674-5817.2024.132.
图 1 月经周期内雌孕激素水平变化示意图和异常子宫出血大鼠模型制备流程图注：图中曲线为正常人体月经周期中雌激素和孕激素水平的变化。图中流程为制备异常子宫出血大鼠模型的方案。
Figure 1 Schematic diagram of estrogen and progesterone level fluctuations during the menstrual cycle and flowchart of the preparation process for a rat model of abnormal uterine bleedingNote： Curves in the figure represent the changes in estrogen and progesterone levels during the normal human menstrual cycle. The process in the figure illustrates the protocol for preparing a rat model of abnormal uterine bleeding.
图 2 异常子宫出血模型大鼠动情周期改变的阴道脱落细胞涂片检测（亚甲蓝染色，×200）注：A，正常对照组一只代表性大鼠在一个动情周期内阴道脱落细胞的形态变化（1、2、3、4 d分别为动情前期、动情期、动情后期和动情间期，呈周期性改变）；B，模型组一只代表性大鼠从卵巢切除、激素诱导到孕激素撤退的阴道脱落细胞形态变化（1、2、3、4 d分别为动情间期、动情前期、动情期和动情期，呈非周期性改变）。图片中黑色箭头（?）指向有核上皮细胞，星号（*）标记为角化上皮细胞，方框（□）内为白细胞。图中比例尺为50 μm。
Figure 2 Detection of changes in the estrous cycle in abnormal uterine bleeding model rats using vaginal exfoliated cell smear （methylene blue staining， ×200）Note： A， Morphological changes of vaginal exfoliated cells of a representative rat in the normal control group during one estrous cycle （Days 1， 2， 3， and 4 correspond to proestrus， estrus， metestrus， and diestrus， respectively， showing cyclical changes）； B， Morphological changes of vaginal exfoliated cells of a representative rat in the model group from ovariectomy， hormone induction to progesterone withdrawal （Days 1， 2， 3， and 4 correspond to diestrus， proestrus， estrus， and estrus， respectively， showing a non-cyclic pattern）. In figures， black arrows （?） indicate nucleated epithelial cells， asterisks （*） mark keratinized epithelial cells， and boxes （□） denote white blood cells. In figures， the scale bar is 50 μm.
图3 异常子宫出血模型大鼠的子宫外观、出血情况和内膜组织病理变化注：A，正常对照大鼠的子宫外观和子宫内膜组织HE染色图片；B～F，异常子宫出血模型大鼠孕激素撤退0、12、24、36、48 h的子宫外观和收集每12 h子宫出血的阴道棉球（右下角）、子宫内膜组织HE染色图片。HE染色的低倍镜图片中两个星号（*）分别标记为两个高倍镜观察处，黑色箭头（?）指向内膜上皮、腺体、坏死的间质、血管和出血等结构和病理现象。HE染色图中比例尺从左到右分别为500 μm、50 μm和50 μm。
Figure 3 Uterine morphology， bleeding patterns， and histopathological changes of endometrial tissues in abnormal uterine bleeding model ratsNote： A， Uterine morphology and the HE-stained images of endometrial tissue in normal control rats； B-F， The uterine morphology in AUB model rats at 0 h， 12 h， 24 h， 36 h， and 48 h after progesterone withdrawal， along with vaginal cotton balls collected for uterine bleeding assessment every 12 hours （lower right corner）， and the HE-stained images of endometrial tissue at the corresponding time points. The two asterisks （*） in each low-magnification HE-stained image indicate the two areas observed under high magnification， and the black arrows （?） point to the structures and pathological phenomena such as the endometrial epithelium， glands， necrotic stroma， blood vessels， and bleeding. In the HE-stained images， the scale bars from left to right column are 500 μm， 50 μm and 50 μm， respectively.
图 4 异常子宫出血模型大鼠的血清性激素水平、子宫血管和间质的损伤修复情况和血管收缩功能的变化注：A，ELISA检测正常对照大鼠和异常子宫出血模型大鼠孕激素撤退36 h血清中性激素包括FSH、E2、LH和PROG的水平（n=6）；B，免疫组织化学染色检测两组大鼠子宫组织中血管内皮表达蛋白即血小板-内皮细胞黏附分子-1（CD31）、血管生成蛋白即血管内皮生长因子（VEGF）、间质损伤和修复蛋白即基质金属蛋白酶-9（MMP-9）的表达及其结果分析（n=3，照片图比例尺为100 μm），以及大鼠子宫内膜TUNEL染色结果及其阳性细胞占比统计［n=3，低倍镜图片（比例尺为100 μm）中星号（*）标记为高倍镜（比例尺为25 μm）观察处］；C，蛋白质印迹法检测两组大鼠子宫组织中成纤维细胞生长因子2（FGF2）和内皮素-1（ET-1）的表达及其相对量分析（n=3，数据表示为平均值±标准误；与正常对照组比较，nsP＞0.05，*P<0.05，**P<0.01）。
Figure 4 Changes in serum sex hormone levels， injury and repair of uterus blood vessels and stroma， and vascular contractile function of uterus in abnormal uterine bleeding model ratsNote： A， ELISA was used to measure serum levels of sex hormones， including FSH， E2， LH， and PROG， in normal control rats and the AUB model rats at 36 h after progesterone withdrawal （n=6）. B， Immunohistochemistry was performed to assess the expression of vascular endothelial marker platelet endothelial cell adhesion molecule-1 （CD31）， angiogenesis-related protein vascular endothelial growth factor （VEGF）， and stromal injury/repair protein matrix metalloproteinase-9 （MMP-9） in uterine tissues of both groups，along with statistical analysis of the results （n=3； scale bars： 100 μm）. Additionally， TUNEL staining of rat endometrium was conducted， and the percentage of positive cells was quantified ［n=3； asterisks （*） in low-magnification images （scale bars： 100 μm） indicate regions selected for high-magnification observation （scale bars： 25 μm）］. C， Western blotting was employed to detect the expression of fibroblast growth factor 2 （FGF2） and endothelin-1 （ET-1） in uterine tissues of both groups， along with relative quantification （n=3； data presented as mean ± standard error （SE）； Compared with normal control group， nsP＞0.05， *P<0.05， **P<0.01）.
图 5 异常子宫出血模型大鼠子宫组织中差异表达基因的转录组学分析注：A，转录组学测序正常对照大鼠和异常子宫出血模型大鼠孕激素撤退36 h（Model-36 h）样本的基因数目（与正常对照组比较，****P<0.000 1）；B，主成分分析结果；C，两组间表达基因差异的Venn图［图中蓝色区域表示Model-36 h相比正常对照组表达显著降低（Down）的基因集合，红色区域表示Model-36 h相比正常对照组表达显著升高（Up）的基因集合］；D，差异表达基因分布火山图（下调差异表达基因中符合差异倍数筛选条件的用蓝色表示，不符合差异倍数筛选条件的用浅蓝色表示；上调差异表达基因中符合差异倍数筛选条件的用红色表示，不符合差异倍数筛选条件的用浅红色表示；差异不显著的表达基因用灰色表示。图中标注了部分差异倍数较高的下调和上调差异表达基因）；E，差异表达基因分组聚类热图，图中颜色深浅代表数据点的数值高低（根据相似性进行分组聚类，图中标注了差异倍数较高的上调和下调基因）。
Figure 5 Transcriptomic analysis of differentially expressed genes in uterine tissue of abnormal uterine bleedingmodel ratsNote： A， The number of genes in rat samples from the normal control rats and the AUB model rats at 36 h after progesterone withdrawal （Model-36 h）（compared with normal control group， ****P<0.000 1）； B， Results of principal component analysis； C， Venn diagram showing the differences in expressed genes between the two groups ［The blue area represents the gene set with significantly decreased expression （Down） in the Model-36 h compared to normal control group， while the red area represents the gene set with significantly increased expression （Up） in the Model-36 h compared to normal control group］； D， Volcano plot of differentially expressed genes （down-regulated differentially expressed genes meeting fold change criteria in blue， non-meeting fold change criteria in light blue； up-regulated differentially expressed genes meeting criteria in red， non-meeting criteria in light red； non-significantly expressed genes in gray. The plot labels some of the differentially expressed genes with higher fold changes， including both down-regulated and up-regulated ones）； E， Differentially expressed gene clustering heatmap by group， where the intensity of color represents the value of data points （grouping and clustering are based on similarity， and genes with higher fold changes in up-regulation and down-regulation are labeled in the heatmap）.
编号 No. | 基因符号 Gene symbol | log2差异倍数 log2(fold change) | q值 q-value | 功能概述 Summary |
|---|---|---|---|---|
| Up-regulated genes | ||||
| 1 | Scin | 4.173 | 4.546×10-191 | Predicted to enable actin filament binding activity and phosphatidylinositol-4,5-bisphosphate binding activity. etc. |
| 2 | Btc | 5.961 | 7.347×10-158 | Enables epidermal growth factor receptor binding activity and growth factor activity. etc. |
| 3 | Serpinb11 | 9.021 | 1.630×10-142 | Predicted to enable serine-type endopeptidase inhibitor activity. etc. |
| 4 | Slc16a12 | 6.266 | 9.424×10-126 | Enables creatine transmembrane transporter activity. etc. |
| 5 | Tprg1 | 8.356 | 2.229×10-118 | Predicted to be active in cytoplasm. etc. |
| 6 | Olfm4 | 8.147 | 2.346×10-108 | Predicted to enable cadherin binding activity and structural molecule activity. etc. |
| 7 | Tnfaip6 | 6.344 | 3.099×10-93 | Predicted to enable several functions, including carboxylesterase activity. etc. |
| 8 | Nck1 | 2.451 | 1.127×10-84 | Predicted to enable several functions, including eukaryotic initiation factor eIF2 binding activity. etc. |
| 9 | Actn4 | 1.188 | 1.391×10-83 | Enables ubiquitin protein ligase binding activity. etc. |
| 10 | Tmbim1 | 3.027 | 1.062×10-82 | Predicted to enable calcium channel activity and death receptor binding activity. etc. |
| Down-regulated genes | ||||
| 1 | Gstm5 | -4.393 | 3.077×10-61 | Enables glutathione transferase activity and identical protein binding activity. etc. |
| 2 | Armh4 | -5.671 | 4.422×10-54 | Predicted to enable TORC2 complex binding activity. etc. |
| 3 | LOC102548820 | -7.032 | 2.774×10-52 | - |
| 4 | Arg2 | -4.338 | 1.561×10-50 | Enables arginase activity and nitric-oxide synthase binding activity. etc. |
| 5 | Frem2 | -6.413 | 6.963×10-47 | Predicted to be involved in anatomical structure morphogenesis and cell adhesion. etc. |
| 6 | Mppe1 | -1.346 | 1.575×10-44 | Predicted to enable GPI anchor binding activity. etc. |
| 7 | Lef1 | -3.875 | 3.022×10-43 | Predicted to enable several functions, including DNA binding activity. etc. |
| 8 | Smad9 | -4.048 | 8.538×10-42 | Predicted to enable DNA-binding transcription factor activity, RNA polymerase Ⅱ-specific. etc. |
| 9 | Miga1 | -1.944 | 4.052×10-41 | Predicted to enable protein heterodimerization activity and protein homodimerization activity. etc. |
| 10 | Bmpr1b | -2.515 | 1.387×10-38 | Predicted to enable several functions, including ATP binding activity. etc. |
表1 异常子宫出血模型大鼠与正常对照大鼠子宫组织的差异表达基因中前10个上调和前10个下调基因的基本信息
Table 1 Basic information of the top 10 up-regulated and the top 10 down-regulated differentially expressed genes in uterine tissues between abnormal uterine bleeding model rats and normal control rats
编号 No. | 基因符号 Gene symbol | log2差异倍数 log2(fold change) | q值 q-value | 功能概述 Summary |
|---|---|---|---|---|
| Up-regulated genes | ||||
| 1 | Scin | 4.173 | 4.546×10-191 | Predicted to enable actin filament binding activity and phosphatidylinositol-4,5-bisphosphate binding activity. etc. |
| 2 | Btc | 5.961 | 7.347×10-158 | Enables epidermal growth factor receptor binding activity and growth factor activity. etc. |
| 3 | Serpinb11 | 9.021 | 1.630×10-142 | Predicted to enable serine-type endopeptidase inhibitor activity. etc. |
| 4 | Slc16a12 | 6.266 | 9.424×10-126 | Enables creatine transmembrane transporter activity. etc. |
| 5 | Tprg1 | 8.356 | 2.229×10-118 | Predicted to be active in cytoplasm. etc. |
| 6 | Olfm4 | 8.147 | 2.346×10-108 | Predicted to enable cadherin binding activity and structural molecule activity. etc. |
| 7 | Tnfaip6 | 6.344 | 3.099×10-93 | Predicted to enable several functions, including carboxylesterase activity. etc. |
| 8 | Nck1 | 2.451 | 1.127×10-84 | Predicted to enable several functions, including eukaryotic initiation factor eIF2 binding activity. etc. |
| 9 | Actn4 | 1.188 | 1.391×10-83 | Enables ubiquitin protein ligase binding activity. etc. |
| 10 | Tmbim1 | 3.027 | 1.062×10-82 | Predicted to enable calcium channel activity and death receptor binding activity. etc. |
| Down-regulated genes | ||||
| 1 | Gstm5 | -4.393 | 3.077×10-61 | Enables glutathione transferase activity and identical protein binding activity. etc. |
| 2 | Armh4 | -5.671 | 4.422×10-54 | Predicted to enable TORC2 complex binding activity. etc. |
| 3 | LOC102548820 | -7.032 | 2.774×10-52 | - |
| 4 | Arg2 | -4.338 | 1.561×10-50 | Enables arginase activity and nitric-oxide synthase binding activity. etc. |
| 5 | Frem2 | -6.413 | 6.963×10-47 | Predicted to be involved in anatomical structure morphogenesis and cell adhesion. etc. |
| 6 | Mppe1 | -1.346 | 1.575×10-44 | Predicted to enable GPI anchor binding activity. etc. |
| 7 | Lef1 | -3.875 | 3.022×10-43 | Predicted to enable several functions, including DNA binding activity. etc. |
| 8 | Smad9 | -4.048 | 8.538×10-42 | Predicted to enable DNA-binding transcription factor activity, RNA polymerase Ⅱ-specific. etc. |
| 9 | Miga1 | -1.944 | 4.052×10-41 | Predicted to enable protein heterodimerization activity and protein homodimerization activity. etc. |
| 10 | Bmpr1b | -2.515 | 1.387×10-38 | Predicted to enable several functions, including ATP binding activity. etc. |
图6 异常子宫出血模型大鼠子宫组织中差异表达基因的转录组学分析注：A，上调差异表达基因的GO功能分析；B，下调差异表达基因的GO功能分析；C，上调差异表达基因的KEGG富集分析；D，下调差异表达基因的KEGG富集分析。
Figure 6 Transcriptomic analysis of differentially expressed genes in uterine tissue of model rats with abnormal uterine bleedingNote： A， GO functional analysis of up-regulated differentially expressed genes； B， GO functional analysis of down-regulated differentially expressed genes； C， KEGG enrichment analysis of up-regulated differentially expressed genes； D， KEGG enrichment analysis of down-regulated differentially expressed genes.
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