Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC136910.15690/vramn1369OBSTETRICS AND GYNAECOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ АКУШЕРСТВА И ГИНЕКОЛОГИИResearch ArticleThe Role of Extracellular Vesicles of Various Origins in the Development of PreeclampsiaРоль экстраклеточных везикул различного происхождения в развитии преэклампсииhttps://orcid.org/0000-0001-9459-569857191960907AAI-6271-20208295-9290NikolaevaMariya G.НиколаеваМария Геннадьевна
Russian Federation

MD, PhD, Associate Professor

доктор медицинских наук, доцент кафедры акушерства и гинекологии с курсом ДПО

nikolmg@yandex.ruhttps://orcid.org/0000-0003-0695-61459359-1428TerekhinaVasilisa U.ТерехинаВасилиса Юрьевна
Russian Federation

assistant

ассистент кафедры акушерства и гинекологии с курсом ДПО

vasutka_07@mail.ruhttps://orcid.org/0000-0002-0967-611737102157300AAB-8493-20206231-4604KudinovAlexey V.КудиновАлексей Владимирович
Russian Federation

candidate of biological sciences

кандидат биологических наук, старший научный сотрудник

kudinovalexej@gmail.comhttps://orcid.org/0000-0002-8413-54846603848680M-7923-20158464-9030MomotAndrey P.МомотАндрей Павлович
Russian Federation

MD, PhD, Professor

доктор медицинских наук, профессор

xyzan@yandex.ruAltai State Medical UniversityАлтайский Государственный медицинский УниверситетNational Research Center for HematologyНациональный медицинский исследовательский центр гематологииAltai State Medical UniversityАлтайский государственный медицинский университетNational Medical Research Center for HematologyНациональный медицинский исследовательский центр гематологии030920217632372430706202003052021Copyright ©; 2021, "Paediatrician" Publishers LLCCopyright ©; 2021, Издательство "Педиатръ"2021"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/article/view/1369

Pre-eclampsia is a clinically unfavorable pregnancy outcome that determines the main indicators of maternal and/or perinatal morbidity and mortality. According to modern concepts, the placenta plays a central role in the development of PE, while intercellular and intervesicular communications involving extracellular vesicles (EVs, extracellular vesicles) initiate a cascade of various biological effects, determining the mechanisms of ontogenesis of the gestational process in normal and pathological conditions. Achievements in studies of extracellular vesicles (EVs, extracellular vesicles) are of particular interest both to clinicians and to researchers studying the pathophysiology of gestational complications. Extracellular vesicles (EVs) in preeclampsia are produced both by scintiotrophoblast and the maternal body - blood cells (platelets, red blood cells, white blood cells) and the cardiovascular (vascular endothelium, smooth muscle) system. Changes in the concentration of these EVs can contribute to the implementation of preeclampsia, enhancing the pro-inflammatory and procoagulant states inherent in the gestation process. This review focuses on freely available information on the possible interactions between placental and maternal EVs. Understanding the contribution of EVs to the development of preeclampsia can help to deepen knowledge about the pathogenesis of this pathology and determine the diagnostic and prognostic significance of extracellular vesicles as biomarkers.

Преэклампсия – это клинически неблагоприятный исход беременности, определяющий основные показатели материнской и/ или перинатальной заболеваемости и смертности. Согласно современным представлениям, центральная роль в развитии преэклампсии принадлежит плаценте, при этом межклеточные и межвезикулярные коммуникации с участием экстраклеточных везикул (extracellular vesicles, EVs) инициируют целый каскад различных биологических эффектов, определяя механизмы онтогенеза гестационного процесса в норме и патологии. Экстраклеточные везикулы (EVs) при преэклампсии вырабатываются как синцитиотрофобластом, так и материнским организмом — клетками кровеносной (тромбоциты, эритроциты, лейкоциты) и сердечно-сосудистой (эндотелий сосудов, гладкомышечная мускулатура) систем. Изменения концентрации этих EVs в плазме крови, могут способствовать реализации преэклампсии, усиливая провоспалительные и прокоагулянтные состояния, свойственные процессу гестации. В настоящем обзоре основное внимание уделяется имеющейся в свободном доступе информации о возможных взаимодействиях между EVs плацентарного и материнского происхождения, а также о влиянии EVs различного происхождения на гемостатический баланс. Понимание вклада EVs в развитие преэклампсии может способствовать углублению знаний о ее патогенезе и определить диагностическую и прогностическую значимость экстраклеточных везикул в качестве биомаркеров.

extracellular vesiclespreeclampsiascintiotrophoblasttissue factorэкстраклеточные везикулыпреэклампсиясинцитиотрофобласттканевой факторLa Rocca C, Carbone F, Longobardi S, Matarese G. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol Lett. 2014;162(1):41–48. doi: https://doi.org/10.1016/J.IMLET.2014.06.013Clemmens H, Lambert DW. Extracellular vesicles: Translational challenges and opportunities. Biochem Soc Trans. 2018;46(5):1073–1082. doi: https://doi.org/10.1042/BST20180112Pieragostino D, Lanuti P, Cicalini I, et al. Proteomics characterization of extracellular vesicles sorted by flow cytometry reveals a disease-specific molecular cross-talk from cerebrospinal fluid and tears in multiple sclerosis. J Proteom. 2019;204:103403. doi: https://doi.org/10.1016/j.jprot.2019.103403Grande R, Dovizio M, Marcone S, et al. Platelet-Derived Microparticles from Obese Individuals: Characterization of Number, Size, Proteomics, and CrosstalkWith Cancer and Endothelial Cells. Front Pharmacol. 2019;10:7. doi: https://doi.org/10.3389/fphar.2019.00007Jaiswal R, Sedger LM. Intercellular Vesicular Transfer by Exosomes, Microparticles and Oncosomes — Implications for Cancer Biology and Treatments. Front Oncol. 2019;9:125. doi: https://doi.org/10.3389/fonc.2019.00125Willms E, Cabañas C, Mäger I, et al. Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression. Front Immunol. 2018;9:738. doi: https://doi.org/10.3389/fimmu.2018.00738Kakarla R, Hur J, Kim YJ, et al. Apoptotic cell-derived exosomes: Messages from dying cells. Exp Mol Med. 2020;52(1):1–6. doi: https://doi.org/10.1038/s12276-019-0362-8Théry C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750. doi: https://doi.org/10.1080/20013078.2018.1535750Klein-Scory S, Tehrani MM, Eilert-Micus C, et al. New insights in the composition of extracellular vesicles from pancreatic cancer cells: Implications for biomarkers and functions. Proteome Sci. 2014;12(1):50. doi: https://doi.org/10.1186/s12953-014-0050-5Кубатиев А.А., Боровая Т.Г., Жуковицкая В.Г., и др. Микрочастицы тромбоцитов: образование и свойства // Патогенез. — 2017. — Т. 15. — № 2. — С. 4–13. [Kubatiev AA, Borovaya TG, ZHukovickaya VG, i dr. Mikrochasticy trombocitov: obrazovanie i svojstva. Patogenez. 2017;15(2):4–13. (In Russ.)] doi: https://doi.org/10.25557/GM.2017.2.7296Пантелеев М.А., Абаева А.А., Баландина А.Н., и др. Внеклеточные везикулы плазмы крови: состав, происхождение, свойства // Биологические мембраны. — 2017. — Т. 34. — № 3. — С. 155–161. [Panteleev MA, Abaeva AA, Balandina AN, i dr. Vnekletochnye vezikuly plazmy krovi: sostav, proiskhozhdenie, svojstva. Biologicheskie Membrany. 2017;34(3):155–161. (In Russ.)] doi: https://doi.org/10.7868/S0233475517030069Керкешко Г.О., Кореневский А.В., Соколов Д.И., Сельков С.А. Роль взаимодействия экстраклеточных микровезикул трофобласта с клетками иммунной системы и эндотелия в патогенезе преэклампсии // Медицинская иммунология. — 2018. — Т. 20. — № 4. — С. 485–514. [Kerkeshko GO, Korenevskij AV, Sokolov DI, Sel’kov SA. Rol’ vzaimodejstviya ekstrakletochnyh mikrovezikul trofoblasta s kletkami immunnoj sistemy i endoteliya v patogeneze preeklampsii. Medicinskaya Immunologiya. 2018;20(4):485–514. (In Russ.)] doi: https://doi.org/10.15789/1563-0625-2018-4-485-514Marques FK, Campos FM, Filho OA, et al. Circulating microparticles in severe preeclampsia. Clin Chim Acta. 2012;24(414):253–258. doi: https://doi.org/10.1016/j.cca.2012.09.023Mikhailova VA, Ovchinnikova OM, Zainulina MS, et al. Detection of microparticles of leukocytic origin in the peripheral blood in normal pregnancy and preeclampsia. Bull Exp Biol Med. 2014;157(6):751– 756. doi: https://doi.org/10.1007/s10517-014-2659-xSalomon C, Guanzon D, Scholz-Romero K, et al. Placental Exosomes as Early Biomarker of Preeclampsia: Potential Role of Exosomal MicroRNAs Across Gestation. J Clin Endocrinol Metab. 2017;102;3182–3194. doi: https://doi.org/10.1210/jc.2017-00672Zhang Y, Zhao C, Wei Y, et al. Increased circulating microparticles in women with preeclampsia. Int J Lab Hematol. 2018;40(3):352–358. doi: https://doi.org/10.1111/ijlh.12796McElrath TF, Cantonwine DE, Gray KJ, et al. Late first trimester circulating microparticle proteins predict the risk of preeclampsia < 35 weeks and suggest phenotypic differences among affected cases. Sci Rep. 2020;10(1):17353. doi: https://doi.org/10.1038/s41598-020-74078-wGoswami D, Tannetta DS, Magee LA, et al. Excess syncytiotrophoblast microparticle shedding is a feature of early-onset pre-eclampsia, but not normotensive intrauterine growth restriction. Placenta. 2006;27(1):56–61. doi: https://doi.org/10.1016/j.placenta.2004.11.007Verma S, Pillay P, Naicker T, et al. Placental hypoxia inducible factor-1α & CHOP immuno-histochemical expression relative to maternal circulatory syncytiotrophoblast micro-vesicles in preeclamptic and normotensive pregnancies. Eur J Obstet Gynecol Reprod Biol. 2018;220:18–24. doi: https://doi.org/10.1016/j.ejogrb.2017.11.004Jadli A, Ghosh K, Damania K, et al. Prediction of preeclampsia using combination of biomarkers at 18–23 weeks of gestation: A nested case-control study. Pregnancy Hypertens. 2019;17:20–27. doi: https://doi.org/10.1016/j.preghy.2019.04.006Campello E, Spiezia L, Radu CM, et al. Circulating microparticles in umbilical cord blood in normal pregnancy and pregnancy with preeclampsia. Thromb Res. 2015;136(2):427–431. doi: https://doi.org/10.1016/j.thromres.2015.05.029Lok CA, Nieuwland R, Sturk A, et al. Microparticle-associated P-selectin reflects platelet activation in preeclampsia. Platelets. 2007;18(1):68–72. doi: https://doi.org/10.1080/09537100600864285Kohli S, Ranjan S, Hoffmann J, et al. Maternal extracellular vesicles and platelets promote preeclampsia via inflammasome activation in trophoblasts. Blood. 2016;128(17):2153–2164. doi: https://doi.org/10.1182/blood-2016-03-705434Faas MM, de Vos P. Maternal monocytes in pregnancy and preeclampsia in humans and in rats. J Reprod Immunol. 2017;119:91–97. doi: https://doi.org/10.1016/j.jri.2016.06.009Dignat-George F, Boulanger CM. The many faces of endothelial microparticles. Arterioscler Thromb Vasc Biol. 2011;31:27–33. doi: https://doi.org/10.1161/ATVBAHA.110.218123Petrozella L, Mahendroo M, Timmons B, et al. Endothelial microparticles and the antiangiogenic state in preeclampsia and the postpartum period. Am J Obstet Gynecol. 2012;20(2):140.e20–6. doi: https://doi.org/10.1016/j.ajog.2012.06.011Perez-Gonzalez R, Gauthier SA, Kumar A, et al. The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J Biol Chem. 2012;287(51):43108–43115.Schmorl G. Pathologisch-anatomischeuntersuchungenuber puerperal-eklampsie (pathological and anatomical examinations of puerperal-eclampsia). Leipzig: FCW Vogel; 1893:106.Chua S, Wilkins T, Sargent I, Redman C. Trophoblast deportation in pre-eclamptic pregnancy. Br J Obstet Gynaecol. 1991;98(10):973–979. doi: https://doi.org/10.1111/j.1471-0528.1991.tb15334.xIkle FA. Dissemination of syncytial trophoblastic cells in the maternal blood stream during pregnancy. Bull Schweiz Akad Med Wiss. 1964;20:62–72.Милованов А.П., Волощук И.Н. Депортированный синцитиотрофобласт и плацентарные микрочастицы в организме матери при нормальной беременности и преэклампсии (28 лет спустя) // Архив патологии. — 2017. — Т. 79. — № 1. — С. 61–67. [Milovanov AP, Voloshchuk IN. Deportirovannyj sincitiotrofoblast i placentarnye mikrochasticy v organizme materi pri normal’noj beremennosti i preeklampsii (28 let spustya). Arhiv Patologii. 2017;79(1):61–67. (In Russ.)] doi: https://doi.org/10.17116/patol201779161-67Tannetta DS, Hunt K, Jones CI, et al. Syncytiotrophoblast extracellular vesicles from preeclampsia placentas differentially affect platelet function. PLoS One. 2015;10(11):e0142538. doi: https://doi.org/10.1371/journal.pone.0142538Salomon C, Torres MJ, Kobayashi M, et al. A gestational profile of placental exosomes in maternal plasma and their effects on endothelial cell migration. PLoS One. 2014;9(6):e98667. doi: https://doi.org/10.1371/journal.pone.0098667Morgan TK. Cell- and size-specific analysis of placental extracellular vesicles in maternal plasma and pre-eclampsia. Transl Res. 2018;201:40–48. doi: https://doi.org/10.1016/j.trsl.2018.08.004Motta-Mejia C, Kandzija N, Zhang W, et al. Placental Vesicles Carry Active Endothelial Nitric Oxide Synthase and Their Activity is Reduced in Preeclampsia. Hypertension. 2017;70:372–381. doi: https://doi.org/10.1161/HYPERTENSIONAHA.117.09321Takov K, He Z, Johnston HE, et al. Small extracellular vesicles secreted from human amniotic fluid mesenchymal stromal cells possess cardioprotective and promigratory potential. Basic Res Cardiol. 2020;115:26. doi: https://doi.org/10.1007/s00395-020-0785-3Collett GP, Redman CW, Sargent IL, Vatish M. Endoplasmic reticulum stress stimulates the release of extracellular vesicles carrying danger-associated molecular pattern (DAMP) molecules. Oncotarget. 2018;9(6):6707–6717. doi: https://doi.org/10.18632/oncotarget.24158Leung DN, Smith SC, To KF, et al. Increased placental apoptosis in pregnancies complicated by preeclampsia. Am J Obstet Gynecol. 2001;184(6):1249–1250. doi: https://doi.org/10.1067/mob.2001.112906Pillay P, Maharaj N, Moodley J, Mackraj I. Placental exosomes and pre-eclampsia: Maternal circulating levels in normal pregnancies and, early and late onset pre-eclamptic pregnancies. Placenta. 2016;46:18–25.Lau SY, Barrett CJ, Guild SJ, Chamley LW. Necrotic trophoblast debris increases blood pressure during pregnancy. J Reprod Immunol. 2013;97(2):175–182. doi: https://doi.org/10.1016/j.jri.2012.12.005Zhang L, Wang Y, Liao AH. Quantitative abnormalities of fetal trophoblast cells in maternal circulation in preeclampsia. Prenat Diagn. 2008;28(12):1160–1166. doi: https://doi.org/10.1002/pd.5521Orozco AF, Jorgez CJ, Ramos-Perez WD, et al. Placental release of distinct DNA-associated microparticles into maternal circulation: reflective of gestation time and preeclampsia. Placenta. 2009;30(10):891–897. doi: https://doi.org/10.1016/j.placenta.2009.06.012Baig S, Kothandaraman N, Manikandan J, et al. Proteomic analysis of human placental syncytiotrophoblast microvesicles in preeclampsia. Clin Proteomics. 2014;11(1):40. doi: https://doi.org/10.1186/1559-0275-11-40Hausvater A, Giannone T, Sandoval Y-HG, Doonan RJ, Antonopoulos CN, Matsoukis IL, Petridou ET, Daskalopoulou SS. The association between preeclampsia and arterial stiffness. J Hypertens. 2012;30:17–33. doi: https://doi.org/10.1097/HJH.0b013e32834e4b0fGill M, Motta-Mejia C, Kandzija N, et al. Placental Syncytiotrophoblast-Derived Extracellular Vesicles Carry Active NEP (Neprilysin) and Are Increased in Preeclampsia. Hypertension. 2019;73(5):1112–1119. doi: https://doi.org/10.1161/HYPERTENSIONAHA.119.12707Sokolov DI, Ovchinnikova OM, Korenkov DA, et al. Influence of peripheral blood microparticles of pregnant women with preeclampsia on the phenotype of monocytes. Transl Res. 2016;170:112–123. doi: https://doi.org/10.1016/j.trsl.2014.11.009Nair S, Salomon C. Extracellular vesicles and their immunomodulatory functions in pregnancy. Semin Immunopathol. 2018;40:425–437. doi: https://doi.org/10.1007/s00281-018-0680-2Holder BS, Jones T, Sancho Shimizu V, et al. Macrophage exosomes induce placental inflammatory cytokines: a novel mode of maternal-placental messaging. Traffic. 2016;17:168–178. doi: https://doi.org/10.1111/tra.12352Southcombe J, Tannetta D, Redman C, Sargent I. The immunomodulatory role of syncytiotrophoblast microvesicles. PLoS One. 2011;6:e20245. doi: https://doi.org/10.1371/journal.pone.0020245Janes SL, Goodall AH. Flow cytometric detection of circulating activated platelets and platelet hyper-responsiveness in pre-eclampsia and pregnancy. Clin Sci (Lond). 1994;86(6):731–739. doi: https://doi.org/10.1042/cs0860731Chang X, Yao J, He Q, et al. Exosomes from Women with Preeclampsia Induced Vascular Dysfunction by Delivering sFlt (Soluble Fms-Like Tyrosine Kinase)-1 and sEng (Soluble Endoglin) to Endothelial Cells. Hypertension. 2018;72(6):1381–1390. doi: https://doi.org/10.1161/HYPERTENSIONAHA.118.11706Xiao X, Xiao F, Zhao M, et al. Treating normal early gestation placentae with preeclamptic sera produces extracellular micro and nano vesicles that activate endothelial cells. J Reprod Immunol. 2017;120:34–41. doi: https://doi.org/10.1016/j.jri.2017.04.004Момот А.П. Физиологическая беременность как модель несостоявшегося тромбоза // Акушерство и гинекология Санкт-Петербурга. — 2017. — № 2. — С. 44–52. [Momot AP. Fiziologicheskaya beremennost’ kak model’ nesostoyavshegosya tromboza. Akusherstvo i Ginekologiya Sankt-Peterburga. 2017;2:44–52. (In Russ.)]Lacroix R, Dignat George F. Microparticles as a circulating source of procoagulant and fibrinolytic activities in the circulation. Thromb Res. 2012;129(2):27–29. doi: https://doi.org/10.1016/j.thromres.2012.02.025Khaspekova SG, Antonova OA, Shustova ON, et al. Activity of Tissue Factor in Microparticles Produced in vitro by Endothelial Cells, Monocytes, Granulocytes, and Platelets. Biochemistry. 2016;81(2):114–121. doi: https://doi.org/10.1134/S000629791602005XVallier L, Cointe S, Lacroix R, et al. Microparticles and fibrinolysis. Semin Thromb Hemost. 2017;43:129–134. Epub 2016 Dec 6. doi: https://doi.org/10.1055/s-0036-1592301Han C, Wang C, Chen Y, et al. Placenta-derived extracellular vesicles induce preeclampsia in mouse models. Haematologica. 2020; 105(6):1686–1694. doi: https://doi.org/10.3324/haematol.2019.226209Aharon A, Katzenell S, Tamari T, Brenner B. Microparticles bearing tissue factor and tissue factor pathway inhibitor in gestational vascular complications. J Thromb Haemost. 2009;7(6):1047–1050. doi: https://doi.org/10.1111/j.1538-7836.2009.03342.xSzotowski B, Antoniak S, Poller W, et al. Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ Res. 2005;96:1233–1239. doi: https://doi.org/10.1161/01.RES.0000171805.24799.faGardiner C, Tannetta DS, Simms CA, et al. Syncytiotrophoblast microvesicles released from pre-eclampsia placentae exhibit increased tissue factor activity. PloS One. 2011;6(10):e26313. doi: https://doi.org/10.1371/journal.pone.0026313.