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).