Extracellular vesicles as markers and mediators of pregnancy complications: gestational diabetes, pre-eclampsia, preterm birth and fetal growth restriction

Abstract

In high income countries, approximately 10% of pregnancies are complicated by pre-eclampsia (PE), preterm birth (PTB), fetal growth restriction (FGR) and/or macrosomia resulting from gestational diabetes (GDM). Despite the burden of disease this places on pregnant people and their newborns, there are still few, if any, effective ways of preventing or treating these conditions. There are also gaps in our understanding of the underlying pathophysiologies and our ability to predict which mothers will be affected. The placenta plays a crucial role in pregnancy, and alterations in placental structure and function have been implicated in all of these conditions. As extracellular vesicles (EVs) have emerged as important molecules in cell-to-cell communication in health and disease, recent research involving maternal- and placental-derived EV has demonstrated their potential as predictive and diagnostic biomarkers of obstetric disorders. This review will consider how placental and maternal EVs have been investigated in pregnancies complicated by PE, PTB, FGR and GDM and aims to highlight areas where further research is required to enhance the management and eventual treatment of these pathologies.

Keywords: extracellular vesicles; fetal growth restriction; gestational diabetes; placenta; pre-eclampsia; pre-term birth.

Figure 1. Anatomical cross‐section of the human placenta

Adapted from Jansen et al. (2020). Created in Biorender.com.

Figure 2. Schematic diagram of the spiral artery in non‐pregnant state, healthy pregnancy and pregnancies with insufficiently remodelled spiral arteries

A number of other cells in addition to trophoblast cells are thought to be involved in the vascular remodelling of the spiral artery. These include macrophages, uterine natural killer cells (uNK) and uterine mast cells. Adapted from Schumacher et al. (2018). Created in Biorender.com.

Figure 3. Biogenesis of exosomes, microvesicles and apoptotic bodies (small, medium and large EVs; El Andaloussi et al., 2013)

Exosomes range from 30 to 150 nm in diameter and are released from the multivesicular body through fusion with the cell membrane. They show the same membrane orientation as the source cells. Whilst this is also the case with microvesicles (100 nm to 1 μm in diameter), they are formed from a heterogeneous process involving the budding of a cell membrane around the intended contents and the shedding of this membrane. Apoptotic bodies range from 50 to 5000 nm in diameter (Doyle & Wang, 2019) and are formed by the separation of source cell plasma from the cytoskeleton as a reaction to increased hydrostatic pressure after cell contraction (Wickman et al., 2012). Created with Biorender.com.

Figure 4. Oxygen tension in pEV biogenesis and bioactivity

Saloman et al. carried out a study by which they treated cytotrophoblast (CT) cell cultures with different levels of oxygen tension. They found that in the higher oxygen tensions, fewer EVs were secreted by CT cells than in the lower oxygen tensions. They hypothesised that CT‐derived exosomes are formed under hypoxic conditions within early pregnancy in the placenta and that this may be an adaptive response to encourage trophoblast invasion (Salomon et al., 2015). This supports the further investigation into the role of early pregnancy pEVs in both healthy and abnormal pregnancies (Dutta et al., ; Truong et al., 2017). Created in Biorender.com.

Figure 5. Summary of method and findings of Li et al. (2020)

Li et al extracted maternal plasma from 60 mothers who had either a healthy pregnancy or suffered from FGR and pre‐eclampsia. They isolated EVs and lysed them to determine whether their miRNA cargo was altered between each control group and found a collection were up‐ and downregulated in pre‐eclampsia compared to the two control groups. Created in Biorender.com.

Figure 6. Summary of method and findings of Menon, Dixon et al. (2019)

EVs isolated from maternal plasma were collected from four groups: term not in labour (TNIL, n = 13), term in labour (TL, n = 11), preterm premature rupture of membranes (pPROM, n = 8), and preterm birth (PTB, n = 13). SWATH mass spectrometry protieomics were performed displaying notable differences between the four groups. Created in Biorender.com.