Preeclampsia (PE) is a leading cause of maternal and fetal-neonatal deaths, and its pathogenesis has been linked to the involvement of extracellular vesicles (EVs). EVs are a heterogeneous group of cell-originated membranous vesicles including exosomes, microvesicles and apoptotic bodies. EVs transport various bioactive cargos such as lipids, proteins or nucleic acids, and thus mediate cellular communication and contribute to the proper functioning of cells, organs and processes, including normal pregnancy. Numerous studies have reported that EVs are associated with abnormal levels of soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) in PE. EVs isolated from preeclamptic women have been implicated in trophoblast dysfunction and have been reported to activate endothelium, monocytes, and platelets, and to be involved in defective placentation, imbalanced angiogenesis, and intravascular inflammation. When injected into pregnant rodents, these EVs induced hypertension, proteinuria and adverse fetal outcomes. Deciphering the contribution of EVs to PE will advance our current understanding of this disorder and may lead to more clinical strategies for the management of PE. Of note, the composition of EV cargos may be characteristic of the status and stages of gestation, providing researchers the possibility of one day using EVs as novel, non-invasive, biomarkers for early screening of PE. Herein, we reviewed the latest research into EVs with emphasis on their role in the pathogenesis of PE and their applications as biomarkers in the early screening of this pregnancy-specific disorder.
Hypoxia-induced oxidative stress and apoptosis of trophoblast are involved in the pathogenesis of preeclampsia (PE). Extensive research reports that the principal vagal neurotransmitter acetylcholine (ACh) shows anti-oxidative and anti-apoptotic effects in various diseases models. However, the role of ACh in hypoxic trophoblast remains unknown. Here, we examined the apoptotic levels of human placenta and explored the role(s) of ACh on cobalt chloride (CoCl2)-treated (trophoblast-derived) HTR-8/SVneo cells for mimicking hypoxic injuries. Cell counting kit-8 (CCK-8), dihydroethidium (DHE) probe, western blotting, immunofluorescence staining, migration and invasion assay were employed in the current study. Our data showed that placentas from PE women exhibited increased level of reactive oxygen species (ROS) and apoptotic index than those in normal pregnancy. Our in vitro study showed that CoCl2 enhanced ROS generation and apoptosis in HTR-8/SVneo cells through the activation of the p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor-κB (NF-κB) pathway. ACh significantly decreased hypoxia-induced ROS generation and the resulting apoptosis, accompanied by lowered phosphorylation of p38 MAPK and NF-κB. Western blotting analysis further confirmed that ACh decreased the ratio of pp38 MAPK/p38 MAPK, p-NF-κB/NF-κB, Bax/Bcl-2 and cleaved caspase-3/caspase-3. Besides, ACh promoted cell invasion and migration ability under hypoxic conditions. Atropine, the muscarinic receptor antagonist, abolished ACh’s effects mentioned above. Overall, our data showed that ACh exerted protective effects on hypoxia-induced oxidative stress and apoptosis in trophoblast cells via muscarinic receptors, indicating that improved vagal activity may be of therapeutic value in PE management.
Oxidative stress and apoptosis of trophoblasts are involved in preeclampsia (PE). Numerous studies have shown that acetylcholine (ACh), the principal vagal neurotransmitter, plays a crucial role in attenuating oxidative stress, inflammation, and apoptosis in a variety of human diseases. However, the role of ACh in PE management remains unclear. Here, we aimed to determine the effects of ACh on TNF-α-treated human primary trophoblast cells. Western blotting, CCK-8, DHE, TUNEL immunofluorescence staining, transwell assays, and wound-healing assays were performed to evaluate the role of ACh in vitro. We found that both TNF-α expression and the apoptotic index were higher in placentas from preeclamptic women than in normal placentas. TNF-α enhanced oxidative stress and increased the number of TUNEL-positive nuclei, Bax/Bcl-2 ratio, and the cleaved caspase-3/caspase-3 ratio while decreasing cell viability in primary human trophoblast cells. TNF-α promoted cell migration and invasion. PDTC, a selective NF-κB inhibitor, significantly blunted TNF-α-induced effects. ACh treatment attenuated oxidative stress and apoptosis while further promoting migration and invasion of TNF-α-treated primary trophoblast cells. The effects of ACh could be reversed by the muscarinic receptor antagonist atropine. Overall, our findings indicate that ACh significantly ameliorates TNF-α-induced oxidative stress and apoptosis of human primary trophoblast cells via muscarinic receptors. This is the first time that the improvement of vagal activity served as a therapeutic strategy for PE-like trophoblasts, suggesting its potential value in clinical practice.
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