Marisa Pinson

 Introduction.  Preeclampsia (PE) is defined by new onset hypertension and proteinuria by ≥20 weeks of gestation.^1-4 PE occurs in 2-5% of pregnancies and is the leading cause of maternal and fetal morbidity and mortality globally.¹ Currently, the only treatment for PE is delivery of the placenta. The mechanisms behind the development of PE are still being understood.^1-2 It is known that PE develops as a result of dysfunction of placentation and spiral artery development and is associated with a pro-inflammatory and pro-coagulatory state.^3-4 Recently, there is increasing interest in the influence of exosomes in the development of PE due to their role in fetal-maternal communication.^1-4 Furthermore, conditions associated with PE, such as hypoxia and increased fetal hemoglobin (HbF) levels, have been shown to change the quantity and composition of exosomes, potentially influencing their role in normal placentation to favor development of PE.^5-6 Methods.Human first-trimester primary trophoblasts were incubated in 5 mM or 25 mM D-glucose under oxygen tensions of 1%, 3%, and 8% for 48 hrs.⁷ Cytokine content of extracellular vesicles (EVs) was analyzed using protein solution arrays. Term human placental cotyledons were perfused with HbF or medium as a control before miRNA analysis of EVs using qPCR.⁶ Human umbilical vein endothelial cells (HUVECs) were treated with specific factors (VEGF, PlGF, TGFβ) to test the effectiveness of neutralization of the normally disruptive effects of fms-like tyrosine kinase (Flt-1) and endoglin on cell growth.⁸ Results.  Hypoxic and high glucose conditions lead to an increased quantity of EVs expressed and a change to a more pro-inflammatory cytokine profile, reflective of the pro-inflammatory state of PE.⁷ Perfusion of placentas by HbF leads to a decrease in exosomal levels of mir-517and mir-517b (normally expressed in higher levels by the placenta), as well as decreased mir-141 (associated with epithelial-mesenchymal transition).⁶ Treatment of HUVECs with specific factors is able to neutralize Flt-1 and endoglin making the proteins a target in preventing placentation dysfunction.⁸ Conclusions.  Studies have shown that conditions associated with PE are capable of influencing exosome expression.^5-8 These alterations in exosome expression potentially play a role in the development of PE by influencing the levels of cytokines and miRNA within exosomes.^6-7 Differences in normal and PE exosomes can be utilized in the development of new diagnostic techniques, such as checking miRNA levels qPCR of serum exosomes, and therapy targets, such as the neutralization of Flt-1 and endoglin by treatment with VEGF.^6,8

1. Gilani SI, Weissgerber TL, Garovic VD, Jayachandran Preeclampsia and Extracellular Vesicles. Current Hypertension Reports. 2016;18:68.
2. Tannetta D, Masliukaite I, Vatish M, Redman C, Sargent I. Update of syncytiotrophoblast derived extracellular vesicles in normal pregnancy and Journal of Reproductive Immunology. 2017;119:98-106.
3. De Toro J, Herschlik L, Waldner C, Mongini C. Emerging Roles of Exosomes in Normal and Pathological Conditions: New Insights for Diagnosis and Therapeutic Front Immunol. 2015;6:203.
4. Escudero CA, Herlitz K, Troncoso F, et Role of Extracellular Vesicles and microRNAs on Dysfunctional Angiogenesis during Preeclamptic Pregnancies. Frontiers in Physiology. 2016;7:98.
5. Salomon C, Kobayashi M, Ashman K, Sobrevia L, Mitchell MD, Rice Hypoxia-Induced Changes in the Bioactivity of Cytotrophoblast-Derived Exosomes. PLoS ONE. 2013;8(11).
6. Cronqvist T, Saljé K, Familari M, et Syncytiotrophoblast Vesicles Show Altered micro-RNA and Haemoglobin Content after Ex-vivo Perfusion of Placentas with Haemoglobin to Mimic Preeclampsia. PLOS ONE. 2014;9(2):e90020.
7. Rice GE, Scholz-Romero K, Sweeney E, et The Effect of Glucose on the Release and Bioactivity of Exosomes From First Trimester Trophoblast Cells. J Clin Endocrinol Metab. 2015;100(10):E1280-E1288.
8. Tannetta DS, Dragovic RA, Gardiner C, Redman CW, Sargent IL. Characterisation of Syncytiotrophoblast Vesicles in Normal Pregnancy and Pre-Eclampsia: Expression of Flt-1 and PLoS ONE. 2013;8(2).