Physiological uterine activity during pregnancy and parturition
During pregnancy and labour, the myometrium undergoes distinct molecular changes from noncontractile phynotype (quiescence) to contractile phynotype depending on the gestational age (37,50,51). This process of uterine activity during pregnancy and parturition can be divided into at least four separate phases(52–54). The four recognized phases of uterine activity include quiescence, activation, stimulation and involution (figure 2).
In the first phase (uterine quiescence) which occurs in pregnancy, there is increased inhibition of uterine activity by either separate or combined autocrine-paracrine signalling transduction stimulated by pro-pregnancy factors such as progesterone, prostacyclin (PGI2), relaxin, parathyroid hormone-related peptide (PTHrP), calcitonin gene-related peptide, adrenomedullin, vasoactive intestinal peptide (VIP), nitric oxide, and CRH, which maintains the uterus in a relatively quiescent state (52,53,55). This allows angiogenesis and tissue remodelling especially around the placentation site to improve adequate placental circulation, foetal nutrition and intrauterine growth (figure 2) (56). Alteration in the production of these agents during late gestation may lead to the onset of preterm or term labour, whereas administration of these compounds or their analogues may help maintain uterine quiescence. Uterine smooth muscle relaxants act by signalling through binding and activation of G-protein stimulatory (Gαs) subunit of the G-protein coupled receptor (GPCR) located on the surface of the myocytes. Activated GTP bound Gαs activates adenylate cyclase or guanylate cyclase causing increased intracellular concentrations of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). These nucleotides interfere with intracellular calcium release and reduce the activity of myosin light chain kinase (MLCK) which are required for shortening of the myofilaments and smooth muscle contractions (figure 4) (52,53,55).
As pregnancy approaches term, the myometrium transitions from its quiescence state to activation. This second phase of uterine activity is characterised by progesterone diminution to oestrogen and CRH dominance associated with increased mechanical stretch or uterotrophic sensitisation (figure 2) (51,53,55). This leads to increased expression of contraction-associated proteins (CAPs) including connexion 43 (Cx43, a key component of gap junctions), agonist receptors (prostaglandins and oxytocin) as well as increased influx of calcium ions into the uterine myocytes(51–53,55). During the second phase of uterine activity, upregulation of GJA1/Cx43 gene mediate hypersensitivity of receptors to uterotonic agonists such as PGs and oxytocin which generate high intensity and coordinated phasic uterine contractions(55,57). Cx43 is a gap junction channel formed from hexamers of connexion proteins that plays a critical role in cell to cell coupling and generates synchronous myometrial contractions(57,58). It allows direct exchange of macro molecules, ions, and second messengers such as cAMP, cGMP, inositol phosphate and Ca2+ between cells which enable channels control and coordinate cellular activity (figure 4) (58).
Stimulation represents the third phase of uterine activity during parturition and is typified by increased uterine smooth muscle tone stimulated by uterotonins such as PGs, oxytocin, and CRH. This phase is characterised by increased synthesis of pro-inflammatory mediators (i.e. IL-1β, IL-8, TNF-α etc.), prostaglandins and white cell (e.g. monocytes and neutrophiles) infiltration of the uterus, foetal membranes and cervix; activating a biochemical process that triggers inflammatory reactions within the uterus. Production of pro-inflammatory mediators causes release of matrix metalloproteinases which breakdown the extracellular matrix and increased gene expression for prostaglandins in uterine tissues (figure 2). This leads to uterine contractions, cervical remodelling and ripening(51,59,60). Increased expression of prostaglandins receptors and gap junctions also occurs in the third phase of parturition. Prostaglandins stimulate functional fundal contractions, lower segmental contraction of the uterus and facilitate cervical ripening while gap junctions permit cell to cell communication by allowing intercellular exchange of macro molecules such as calcium, cAMPs and cGMPs (figure 4) (59,60).
The last phase of uterine activity is characterised by massive uterine involution to resemble the pregnancy stage and tissue remodelling after delivery of the foetus and placenta, and has been attributed primarily to the release of neuroendocrine oxytocin(51–53,55,60). During this phase, there is a rapid withdrawal of pro-pregnancy factors (e.g. progesterone) that maintains uterine quiescence and increased recruitment of pro-labour factors (e.g. gap junctions, calcium-sensitive potassium channels, and connexions) that stimulate the biochemical changes similar to those occurring in labour (figure 2) (59,61).