Physiological pathways and biological mechanisms of uterine
contraction
Series of physiological events occur before, during and after pregnancy
which modulate myometrial contractility throughout the menstrual cycle
in the non-pregnant uterus, maintenance of pregnancy, promotion of child
birth and enhance involution(40,73,76,77). These events may include both
maternal and foetal characteristics which generate signalling molecules
necessary for the stimulation of myometrial contractions during
labour(73,76). Knowledge about the biological mechanisms and pathways
that control myometrial contraction and relaxation and how these
pathways can be regulated is paramount for clinical practice.
Conventional trials in animal models showed that parturition is
determined by activation of the foetal hypothalamic-pituitary adrenal
(HPA) axis with increased foetal cortisol secretion. Following
mechanical stress, activation of HPA pathway leads to reduction in
maternal progesterone levels and increased levels of oestradiol. This
endocrine imbalance promotes increased intrauterine production of
prostaglandins, cervical softening and the onset of myometrial
contractions (78,79).
The contractile state of the myometrium is determined by the interaction
of the two major muscle proteins, actin and myosin. This interaction of
actin-myosin is influenced by myometrial signalling pathways which are
broadly categorised into signalling cascades regulating intracellular
calcium (Ca2+) concentration and those controlling the contractile
apparatus itself(40,77). Abundant in the plasma membrane of the uterine
myocytes are L-type calcium ion (Ca2+) channels which are ubiquitous,
large conductance, voltage-gated calcium channels (VGCC) (76,80).
Binding of an agonist (e.g. oxytocin) to specific receptor causes
depolarisation of the myocyte’s membrane potential and opening of the
L-type calcium channels leading to rapid influx of extracellular calcium
ions and dramatic rise in intracellular calcium ion
concentration(73,76). The plasma membrane of the myocyte also contain
other types of calcium channels (i.e. T-type calcium channels) which
exhibit faster kinetics and greater conductance than the L-type (figure
4) (76).
Within the myometrium, agonist interaction with GPCR on the plasma
membrane (PM) of myocytes leads to activation of the Gαq subunit of the
trimeric G-protein. Activated Gαq subunit also binds and activates
membrane-bound phospholypase Cβ which hydrolyzes phosphatidylinositol
bisphosphate (PIP2) into inositol-triphosphate (IP3) and diacylglycerol
(DAG)(73,76,77). IP3 interact with IP3-sensitive receptors (IP3-Rs) on
sarcoplasmic reticulum (SR) which causes release of calcium from its
storage sites in the SR into the cytosol. Increased cytosolic calcium
concentration also stimulates the rynodine receptors to cause
Ca2+-induced Ca2+ release (CICR)(40,73,76). Another mechanism, called
store-operated Ca2+ entry (SOCE), also regulates Ca2+ flux occurs when
the intracellular Ca2+ stores in the SR are exhausted, it stimulates the
PM to permit influx of extracellular Ca2+ into the cytosol(76).
Increased concentration of Ca2+ in the cytosol leads to binding of
calcium to calcium-sensitive protein, Calmodulin. The Calcium-Calmodulin
complex activates the enzyme Myosin Light Chain Kinase (MLCK) which in
turn causes increased phosphorylation of Myosin Light Chain (MLC)
leading to actin-myosin cross-bridge formation and activation of the
contractile machinery (figure 4)(40,73,76).
Relaxation of uterine smooth muscles occur when removal of cytosolic
Ca2+ occurs through closure of PM L-type Ca2+ channels, efflux of Ca2+
into the extracellular compartment through Ca2+-ATPase pumps on plasma
membrane and into intracellular Ca2+ stores in SR via SR/ER Ca2+-ATPase
(SERCA) pumps(40,73,76,77). Also, Myosin Light Chain Phosphatase (MLCP)
causes dephosphorylation of the myosin light chain which is regulated by
signalling through the small G-protein rhoA–rho-associated kinase and
protein kinase C (PKC) pathways. Dephosphorylation of the myosin light
chain inhibits actin-myosin cross-bridge formation leading to smooth
muscle relaxation (figure 4) (76).
Conversely, in postterm pregnancy although the actual aetiology is not
yet known, genetics and maternal and fetal factors are implicated in its
pathogenesis(73,81,82). Unlike preterm labour, fetal hypothalamic
pituitary adrenal (HPA) insufficiency and a disorder in placental
sulphatase activity (an X-linked recessive gene disorder) result in
reduced production of eostriol (E3) which plays a fundamental role in
the pathogenesis of postterm pregnancy(81,82). Subsequently, placental
CRH production declines with diminution in the positive feedback
mechanism on the production of foetal adrenal dehydroepiandrosterone
(DHEA). Decreased production of foetal eostriol and cortisol ensue which
interferes with the biological pathways for spontaneous onset of
labour(81).