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).