龚榕铨;曹恒山;马敏;

• 1:扬州大学医学院
• 2:扬州大学附属医院产科

摘要(Abstract)：

子痫前期作为一种妊娠期特有的高血压综合征,严重威胁母婴安全,但目前尚无准确的生物标志物作为诊断依据且其病因和发病机制尚未完全阐明。外泌体是广泛存在于体液中的细胞外囊泡,携带多种蛋白质、脂质和核酸等生物活性分子,具有多种生物学功能,其所携带的miRNA具有特异性、多元性、抗降解、能被稳定检出的特点。研究发现子痫前期患者胎盘组织分泌的外泌体中有多种差异表达的miRNA,表明其可能参与了子痫前期的发生发展,可能作为子痫前期预测的潜在靶点。本文对外泌体源性miRNA的结构、功能及其与子痫前期发病机制的研究进展进行综述,旨在为子痫前期早期预测及诊治提供新思路。

关键词(KeyWords)： 子痫前期;外泌体;mi RNA;滋养细胞;血管生成;母胎免疫调节;炎症反应

Abstract:

Keywords:

基金项目(Foundation): 江苏高校自然科学基金面上项目（20KJD320004）;; 江苏省大学生创新创业训练计划（202011117118Y）;; 江苏省研究生实践创新计划（XSJCX20_036）;; 扬州大学科技创新培育基金（2019CXJ180）;; 江苏省“双创计划”;; 扬州市“绿扬金凤计划”

作者(Author): 龚榕铨;曹恒山;马敏;

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DOI:

参考文献(References)：

• 1 American College of Obstetricians and Gynecologists(ACOG).ACOG practice bulletin No. 202 summary:gestational hypertension and preeclampsia[J]. Obstet Gynecol, 2019, 133(1):211-214.
• 2 Mol BWJ, Roberts CT, Thangaratinam S, et al. Pre-eclampsia[J].Lancet, 2016, 387(10022):999-1011.
• 3 Poon LC, Shennan A, Hyett JA, et al. The International Federation of Gynecology and Obstetrics(FIGO)initiative on pre-eclampsia:a pragmatic guide for first-trimester screening and prevention[J]. Int J Gynaecol Obstet, 2019, 145 Suppl 1(Suppl 1):1-33.
• 4 Cui YJ, Wang W, Dong NZ, et al. Role of corin in trophoblast invasion and uterine spiral artery remodeling in pregnancy[J]. Nature, 2012,484(7393):246-250.
• 5 Steegers EA, von Dadelszen P, Duvekot JJ, et al. Pre-eclampsia[J].Lancet, 2010, 376(9741):631-644.
• 6 Hemmatzadeh M, Shomali N, Yousefzadeh Y, et al. MicroRNAs:small molecules with a large impact on pre-eclampsia[J]. J Cell Physiol, 2020, 235(4):3235-3248.
• 7 Awamleh Z, Gloor GB, Han VKM. Placental microRNAs in pregnancies with early onset intrauterine growth restriction and preeclampsia:potential impact on gene expression and pathophysiology[J]. BMC Med Genomics, 2019, 12(1):91.
• 8 Lip SV, Boekschoten MV, Hooiveld GJ, et al. Early-onset preeclampsia, plasma microRNAs, and endothelial cell function[J].Am J Obstet Gynecol, 2020, 222(5):497.e1-e12.
• 9 Salomon C, Guanzon D, Scholz-Romero K, et al. Placental exosomes as early biomarker of preeclampsia:potential role of exosomal MicroRNAs across gestation[J]. J Clin Endocrinol Metab, 2017, 102(9):3182-3194.
• 10 Li H, Ouyang Y, Sadovsky E, et al. Unique microRNA signals in plasma exosomes from pregnancies complicated by preeclampsia[J].Hypertension, 2020, 75(3):762-771.
• 11 Pillay P, Vatish M, Duarte R, et al. Exosomal microRNA profiling in early and late onset preeclamptic pregnant women reflects pathophysiology[J]. Int J Nanomedicine, 2019, 14:5637-5657.
• 12 Johnstone RM, Adam M, Hammond JR, et al. Vesicle formation during reticulocyte maturation association of plasma membrane activities with released vesicles(exosomes)[J]. J Biol Chem, 1987,262(19):9412-9420.
• 13 Liu H, Wang F, Zhang Y, et al. Exosomal microRNA-139-5p from mesenchymal stem cells accelerates trophoblast cell invasion and migration by motivation of the ERK/MMP-2 pathway via downregulation of protein tyrosine phosphatase[J]. J Obstet Gynaecol Res, 2020, 46(12):2561-2572.
• 14 Valadi H, Ekstr?m K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells[J]. Nat Cell Biol, 2007, 9(6):654-659.
• 15 Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release[J]. Cell Mol Life Sci, 2018, 75(2):193-208.
• 16 Pillay P, Moodley K, Moodley J, et al. Placenta-derived exosomes:potential biomarkers of preeclampsia[J]. Int J Nanomedicine, 2017,12:8009-8023.
• 17 Théry C, Zitvogel L, Amigorena S. Exosomes:composition,bisgenesis and function[J]. Nat Rev Immuol, 2002, 2(8):569-579.
• 18 Zomer A, Vendrig T, Hopmans ES, et al. Exosomes:fit to deliver small RNA[J]. Commun Integr Biol, 2010, 3(5):447-450
• 19 Greening DW, Gopal SK, XU R, et al. Exosomes and their roles in immune regulation and cancer[J]. Semin Cell Dev Biol, 2015, 40:72-81.
• 20 Chiarello DI, Salsoso R, Toledo F, et al. Foetoplacental communication via extracellular vesicles in normal pregnancy and preeclampsia[J]. Mol Aspects Med, 2018, 60:69-80.
• 21 Lee HM, Nguyen DT, Lu LF. Progress and challenge of microRNA research in immunity[J]. Front Genet, 2014, 5:178.
• 22 Arroyo JD, Chevillet JR, Kroh EM, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma[J]. Proc Natl Acad Sci U S A, 2011, 108(12):5003-5008.
• 23 Ge Q, Zhou Y, Lu J, et al. miRNA in plasma exosome is stable under different, storage conditions[J]. Molecules, 2014, 19(2):1568-1575.
• 24 Hromadnikova I, Kotlabova K, Ivankova K, et al. First trimester screening of circulating C19MC microRNAs and the evaluation of their potential to predict the onset of preeclampsia and IUGR[J].PLoS One, 2017, 12(2):e0171756.
• 25 Hromadnikova I, Dvorakova L, Kotlabova K, et al. The prediction of gestational hypertension, preeclampsia and fetal growth restriction via the first trimester screening of plasma exosomal C19MC micro RNAs[J].Int J Mol Sci, 2019, 20(12):2972-2989.
• 26 Zhao XY, Li YM, Chen S, et al. Exosomal encapsulation of miR-125a-5 p inhibited trophoblast cell migration and proliferation by regulating the expression of VEGFA in preeclampsia[J]. Biochem Biophys Res Commun, 2020, 525(3):646-653.
• 27 Motawi TMK, Sabry D, Maurice NW, et al. Role of mesenchymal stem cells exosomes derived microRNAs; miR-136, miR-494 and miR-495 in pre-eclampsia diagnosis and evaluation[J]. Arch Biochem Biophys, 2018, 659:13-21.
• 28 BiróO, Fóthiá, Alasztics B, et al. Circulating exosomal and Argonaute-bound microRNAs in preeclampsia[J]. Gene, 2019, 692:138-144.
• 29 Anton L, Olarerin-George AO, Schwartz N, et al. miR-210 inhibits trophoblsat invasion and is a serum biomarker for preeclampsia[J].Am J Pathol, 2013, 183(5):1437-1445.
• 30 Wang N, Feng Y, Xu J, et al. miR-362-3p regulates cell proliferation,migration and invasion of trophoblastic cells under hypoxia through targeting Pax3[J]. Biomed Pharmacother, 2018, 99:462-468.
• 31 Bai Y, Yang W, Yang HX, et al. Downregulated miR-195 detected in preeclamptic placenta affects trophoblast cell invasion via modulating ActRIIA expression[J]. PLoS One, 2012, 7(6):e38875.
• 32 Xiao J, Tao T, Yin Y, et al. miR-144 may regulate the proliferation,migration and invasion of trophoblastic cells through targeting PTEN in preeclampsia[J]. Biomed Pharmacother, 2017, 94:341-353.
• 33 Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fmslike tyrosine kinase 1(sFlt1)may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia[J]. J Clin Invest, 2003, 111(5):649-658.
• 34 Sandrim VC, Dias MC, Bovolato AL, et al. Plasma from preeclamptic patients induces the expression of the anti-angiogenic miR-195 -5p in endothelial cells[J]. J Cell Mol Med, 2016, 20(6):1198-1200.
• 35 Shen L, Li Y, Li R, et al. Placenta?associated serum exosomal miR?155 derived from patients with preeclampsia inhibits eNOS expression in human umbilical vein endothelial cells[J]. Int J Mol Med, 2018, 41(3):1731-1739.
• 36 Bounds KR, Chiasson VL, Pan LJ, et al. Micro RNAs:new players in the pathobiology of preeclampsia[J]. Front Cardiovasc Med, 2017, 4:60.
• 37 Perez-Sepulveda A, Torres MJ, Khoury M, et al. Innate immune system and preeclampsia[J]. Front Immunol, 2014, 5:244.
• 38 Cornelius DC. Preeclampsia:from inflammation to immunoregulation[J].Clin Med Insights Blood Disord, 2018, 11:1179545X17752325.
• 39 Zhao M, Wang LT, Liang GP, et al. Up-regulation of microRNA-210induces immune dysfunction via targeting FOXP3 in CD4+T cells of psoriasis vulgaris[J]. Clin Immunol, 2014, 150(1):22-30.
• 40 Luo R, Shao X, Xu P, et al. MicroRNA-210 contributes to preeclampsia by downregulating potassium channel modulatory factor1[J]. Hypertension, 2014, 64(4):839-845.
• 41 Pineles BL, Romero R, Montenegro D, et al. Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia[J]. Am J Obstet Gynecol, 2007, 196(3):261 .e1-6.
• 42 Alivernini S, Gremese E, McSharry C, et al. MicroRNA-155-at the critical interface of innate and adaptive immunity in arthritis[J]. Front Immunol, 2018, 8:1932.
• 43 Wang Z, Wang P, Wang Z, et al. MiRNA-548c-5p downregulates inflammatory response in preeclampsia via targeting PTPRO[J]. J Cell Physiol, 2019, 234(7):11149-11155.
• 44 Ma HY, Cu W, Sun YH, et al. MiRNA-203a-3p inhibits inflammatory response in preeclampsia through regulating IL24[J]. Eur Rev Med Pharmacol Sci, 2020, 24(10):5223-5230.