Preeclampsia and syncytiotrophoblast membrane extracellular vesicles (STB-EVs)

Abstract

Preeclampsia (PE) is a hypertensive complication of pregnancy that affects 2–8% of women worldwide and is one of the leading causes of maternal deaths and premature birth. PE can occur early in pregnancy (<34 weeks gestation) or late in pregnancy (>34 weeks gestation). Whilst the placenta is clearly implicated in early onset PE (EOPE), late onset PE (LOPE) is less clear with some believing the disease is entirely maternal whilst others believe that there is an interplay between maternal systems and the placenta. In both types of PE, the syncytiotrophoblast (STB), the layer of the placenta in direct contact with maternal blood, is stressed. In EOPE, the STB is oxidatively stressed in early pregnancy (leading to PE later in gestation- the two-stage model) whilst in LOPE the STB is stressed because of villous overcrowding and senescence later in pregnancy. It is this stress that perturbs maternal systems leading to the clinical manifestations of PE. Whilst some of the molecular species driving this stress have been identified, none completely explain the multisystem nature of PE. Syncytiotrophoblast membrane vesicles (STB-EVs) are a potential contributor to this multisystem disorder. STB-EVs are released into the maternal circulation in increasing amounts with advancing gestational age, and this release is further exacerbated with stress. There are good in vitro evidence that STB-EVs are taken up by macrophages and liver cells with additional evidence supporting endothelial cell uptake. STB-EV targeting remains in the early stages of discovery. In this review, we highlight the role of STB-EVs in PE. In relation to current research, we discuss different protocols for ex vivo isolation of STB-EVs, as well as specific issues involving tissue preparation, isolation (some of which may be unique to STB-EVs), and methods for their analysis. We suggest potential solutions for these challenges.

Unraveling the Multifaceted Roles of Extracellular Vesicles: Insights into Biology, Pharmacology, and Pharmaceutical Applications for Drug Delivery

“…During the late stages of pregnancy, syncytiotrophoblast (STB)-EVs are released directly into the maternal circulation and can be uniquely recognized by a placental alkaline phosphatase [ 83 ]. STB-EVs have been shown to carry several proteins including endoglin, plasminogen activator inhibitor, soluble fms-like kinase (sFlt), and endothelial nitric oxide synthase [ 84 , 85 ], as well as miRNAs [ 86 , 87 ], tRNA [ 88 ], and DNA [ 81 , 89 ]. The physiological functions of peripherally circulating STB-EVs in both in vitro and in vivo investigations are broad and their molecular contents as well as surface markers are powerful and cannot be underestimated.…”

MicroRNA analysis of medium/large placenta extracellular vesicles in normal and preeclampsia pregnancies

“…In contrast, Wei et al explored the role of placenta debris in PE and discovered that PE placenta debris contains a microRNA profile different from that of normal pregnancy ( 13 ). Their EVs were generated with placental explants, a less physiological model than ex-vivo dual lobe perfusion ( 14 ). However, the small RNA composition of the EVs from the explant culture differs from that derived from the ex-vivo dual lobe perfusion.…”

Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates endothelial cells pyroptosis through PDIA4/DDIT4 axis in preeclampsia

“…Nevertheless, the molecular mechanisms underlying the effect of circulating factors remain to be further explored. As evidenced by the increasing number of publications on placental extracellular vesicles (pEVs) which are present in the maternal circulation detected as early as at 6 weeks of gestation, they have been built to link the pathogenesis of pregnancy disorders, especially PE [ 7 ]. EVs are categorized as microvesicles (MVs), exosomes (Exos) and apoptotic bodies (Abs), based on their size and biogenic pathway [ 8 ].…”

“…In addition, MISEV (minimum information for the study of extracellular vesicles) guideline have recommended that physical characteristics, such as size, are used for classify EVs without biogenic synthesis evidence[ 9 ]. In general, EVs have defined as small EVs (sEVs) with size < 220 nm and medium/large EVs (m/lEVs) with size ≥ 220 nm [ 7 ]. Mounting studies have revealed that pEVs markedly elevated in PE patient are engaged in endothelial dysfunction, imbalanced angiogenesis and systemic inflammation, all of which eventually aggravate the disease development [ 10 – 14 ].…”

“…As we know, increased release of pEVs stimulated by trophoblast stress especially oxidative stress are detected in PE women causing maternal systemic manifestations [ 7 ]. Placental oxidative stress is well documented to play a pivotal role in the pathophysiology of PE [ 22 ].…”