Transcriptomic analysis reveals“adipogenesis”in the uterosacral ligaments of postmenopausal women with recurrent pelvic organ prolapse  

转录组学分析揭示复发性盆腔器官脱垂的绝经后妇女存在子宫骶韧带“脂肪化”

作　　者：ZHOU Yanhua YAN Dayu ZHANG Xiulan LI Xuhong YAN Wenguang JIANG Li 周艳华;严大宇;张秀兰;李旭红;严文广;姜丽(中南大学湘雅三医院康复医学科,长沙410013;中南大学湘雅三医院妇产科,长沙410013;中南大学湘雅三医院基础医学博士后工作站,长沙410013)

机构地区：[1]Department of Rehabilitation Medicine,Third Xiangya Hospital,Central South University,Changsha 410013 [2]Department of Obstetrics and Gynecology,Third Xiangya Hospital,Central South University,Changsha 410013 [3]Postdoctoral Research Station of Basic Medicine,Third Xiangya Hospital,Central South University,Changsha 410013,China

出　　处：《中南大学学报(医学版)》2024年第11期1808-1820,共13页Journal of Central South University :Medical Science

基　　金：supported by the Key Research and Development Program of Hunan Province(2023SK2038);the Natural Science Foundation of Hunan Province(2024JJ8121),China。

摘　　要：Objective:Pelvic organ prolapse(POP)is a common condition in postmenopausal women,with an increasing prevalence due to aging.Some women experience POP recurrence after surgical treatment,significantly affecting their physical and mental health.The uterosacral ligament is a critical pelvic support structure.This study aims to investigate the molecular pathological changes in the uterosacral ligament of postmenopausal women with recurrent POP using transcriptomic analysis.Methods:Transcriptomic data of uterosacral ligament tissues were obtained from the public dataset GSE28660,which includes samples from 4 postmenopausal women with recurrent POP,4 with primary POP,and 4 without POP.Differentially expressed genes(DEGs)were identified between recurrent POP and both primary and non-POP groups.Further analysis included intersection analysis of DEGs,gene ontology enrichment,protein protein interaction(PPI)network construction,gene set enrichment analysis(GSEA),single-sample GSEA,and xCell immune cell infiltration analysis to explore molecular pathological changes in recurrent POP.Additionally,histological and molecular differences in the uterosacral ligament were compared between simulated vaginal delivery(SVD)rat models with and without ovariectomy.Results:Compared with primary POP and non-POP groups,recurrent POP exhibited activation of adipogenesis and inflammation-related pathways,while pathways related to muscle proliferation and contraction were downregulated in the uterosacral ligament.Nine key DEGs(ADIPOQ,FABP4,IL-6,LIPE,LPL,PCK1,PLIN1,PPARG,and CD36)were identified,with most enriched in the peroxisome proliferator-activated receptor(PPAR)signaling pathway.These genes were significantly correlated with lipid accumulation,monocyte infiltration,and neutrophil infiltration in the uterosacral ligament.Urodynamic testing revealed that the bladder leak point pressure was significantly higher in ovariectomized SVD rats,both of which had higher values than the sham group.Masson staining showed pronounced adipogenesis in目的:盆腔器官脱垂(pelvic organ prolapse,POP)是绝经后妇女的常见病,随着老龄化时代的到来,其发病率呈逐年上升趋势。部分POP妇女在手术治疗后仍有复发现象,严重影响其身心健康。子宫骶韧带是盆底的重要支持结构之一。本研究拟通过转录组学分析揭示子宫骶韧带在绝经后复发性POP中的分子病理变化。方法:收集公共数据集GSE28660(包含4名绝经后复发性POP、4名原发性POP和4名非POP妇女)中子宫骶韧带的转录组数据,分别计算复发性POP与原发性POP或非POP的差异表达基因。随后,通过差异基因交集分析、基因本体论、蛋白质-蛋白质互作网络构建、基因集富集分析、单样本基因集富集分析以及xCell免疫细胞浸润分析等方法分析复发性POP中子宫骶韧带的分子病理变化。比较卵巢切除和未切除的模拟阴道分娩(simulated vaginal delivery,SVD)大鼠模型的子宫骶韧带的病理结构和分子表达的变化。结果:相比于原发性POP和非POP,复发性POP的子宫骶韧带中脂肪和炎症相关的通路被激活,而与肌肉增殖和收缩相关的通路被抑制。鉴定出的9个关键差异基因(ADIPOQ、FABP4、IL-6、LIPE、LPL、PCK1、PLIN1、PPARG和CD36),大部分富集在过氧化物酶体增殖激活受体(peroxisomeproliferator activated receptor,PPAR)信号通路中,且与子宫骶韧带中的脂肪细胞堆积、单核细胞和中性粒细胞浸润呈显著正相关。尿动力学检测显示卵巢切除SVD大鼠的膀胱漏尿点压力明显高于卵巢未切除SVD大鼠,这2组大鼠的膀胱漏尿点压力均高于假手术组。马松染色结果显示:相比于假手术组和卵巢未切除SVD大鼠,卵巢切除SVD大鼠的子宫骶韧带存在明显的脂肪堆积,胶原纤维和肌纤维成分减少。此外,实时反转录PCR也验证了关键差异基因ADIPOQ、IL-6、PCK1、PLIN1均在卵巢切除SVD大鼠的子宫骶韧带中呈显著高表达。结论:子宫骶韧带出现脂肪堆�

关 键 词：recurrent pelvic organ prolapse uterosacral ligament ADIPOGENESIS INFLAMMATION TRANSCRIPTOMICS 

分 类 号：R711.2[医药卫生—妇产科学]