The Role(s) of Eicosanoids and Exosomes in Human Parturition

Abstract

The roles that eicosanoids play during pregnancy and parturition are crucial to a successful outcome. A better understanding of the regulation of eicosanoid production and the roles played by the various end products during pregnancy and parturition has led to our view that accurate measurements of a panel of those end products has exciting potential as diagnostics and prognostics of preterm labor and delivery. Exosomes and their contents represent an exciting new area for research of movement of key biological factors circulating between tissues and organs akin to a parallel endocrine system but involving key intracellular mediators. Eicosanoids and enzymes regulating their biosynthesis and metabolism as well as regulatory microRNAs have been identified within exosomes. In this review, the regulation of eicosanoid production, abundance and actions during pregnancy will be explored. Additionally, the functional significance of placental exosomes will be discussed.

Keywords: eicosanoids; exosomes; gestation; parturition; pregnancy; preterm labor; prostaglandins.

FIGURE 1

Eicosanoid biosynthesis. The main three pathways involved in eicosanoids biosynthesis from the main precursor, arachidonic acid, are lipoxygenase, cyclooxygenase and cytochrome P450 pathways. The cytochrome P450 pathway produces epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs) from which some products can be further metabolized by cyclooxygenase. Cyclooxygenases (COX1 and 2) can act directly on arachidonic acid to produce the unstable intermediate prostaglandin (PG) H₂ (PGH₂) which then can produce various prostanoids such as PGE₂, PGI₂, PGD₂, and PGF_2α and thromboxane A₂ (TXA₂). Lipoxygenase pathway yields leukotrienes (LTs), such as LTA₄ and LTB₄. Multidrug resistant proteins (MRPs) facilitate the transfer of eicosanoids through the cell membrane. Multiple cellular membrane receptors mediate the action of eicosanoids, such as EP1-4 for PGE₂ and BLT1-2 for LTB₄. [After (Funk, 2001; Strauss and FitzGerald, 2019)].

FIGURE 2

Exosome biogenesis and secretion. The biogenesis of exosomes is initiated with the inward budding of the peripheral membrane into early endosomes (a). Selective exosome packaging with molecules such as protein, RNA and DNA and lipids occurs within the originating cell and cellular compartments such as the Golgi apparatus, endoplasmic reticulum, plasma membrane, nucleus and cytosol. Invagination of the early endosomes into late endosomes (b) allows these diverse molecules to be taken up and individually packaged inside intraluminal vesicles (ILVs), turning the endosomes into multivesicular bodies (MVBs) (c). During the invagination process, proteins are incorporated into the membrane, leaving the cytosolic components to be engulfed into the ILVs. Finally, MVBs either release ILVs intracellularly to be absorbed by lysosomes/autophagosomes (d.1) for degradation or fuse with the plasma membrane to secrete ILVs out into the extracellular space as exosomes (d.2). [After (Kowal et al., 2014)].