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Figure 2: Physiological uterine activity during the non-pregnant state, pregnancy and parturition: During early follicular phase or menses there is increased labour-like uterine contractions modulated by increased prostaglandins and progesterone withdrawal(38,44,45); follicular phase is characterised by progressive increased in wave-like uterine contractions which terminate at pre-ovulation influenced by rise oestrogen levels(41,42,44–46); there is low amplitude contractions during ovulation; luteal phase is characterised by uterine quiescence which favours fertilisation, implantation and placentation. Angiogenesis and tissue remodelling controlled by release of anti-inflammatory mediators (IL-3, IL-4, IL-5, and IL-10) by trophoblast cells occur during the luteal phase. Fertilisation results in increased uterine relaxation controlled by rise in the levels of progesterone. There is profound inhibition of uterine activity during the first phase of pregnancy influenced by pro-pregnancy factors such as progesterone, relaxin, prostacyclin, vasoactive intestinal peptide (VIP), nitric oxide (NO) etc.; second phase of pregnancy is characterised by uterine activation stimulated by progesterone withdrawal to oestrogen and corticotrophin-releasing hormone (CRH) leading to gene expression for contraction-associated proteins (CAPs); third phase is characterised by increased responsiveness to uterotonins and uterine contractions with progressive cervical dilation and effacement; fourth phase is characterised by uterine involution and tissue remodelling governed by withdrawal of pro-pregnancy factors (e. g progesterone, etc.) and recruitment of pro-labour factors (e. g oxytocin) and gap junctions such as connixion43 (cx43)(51,55,59)
Figure 4 : Physiological pathways and biological mechanisms of uterine activity : Binding of pro-pregnancy factors (progesterone, relaxin vasoactive intestinal peptide etc.) to GPCR especially G-protein stimulatory receptor (Gs-R) on plasma membrane (PM) activates adenylate cyclase resulting in rise in cytosolic concentration of cyclic adenosine monophosphate (cAMPs). Increased cAMPs inhibit Ca+ entry and Myosin light chain kinase (MLCK) which leads to uterine muscle relaxation. Pro-labour factor (oxytocin, prostaglandin etc.) binding activates trimeric G-protein coupled receptor (GPCR) results in opening of voltage-gated Ca+ channels (VGCC) in PM. Activated G-protein Gq subunit stimulates phospholypase Cβ (PLCβ) to hydrolyze PIP2 into DAG and IP3, IP3 activates IP3-sensitive receptor at the level of the sarcoplasmic reticulum (SR) to induce calcium ions (Ca2+) release from internal stores. These result in an increased in cytosolic Ca2+ levels which ultimately activates MLCK through the intermediary activation of Ca2+-Calmodulin (Ca2+-CM) complex. MLCK phosphorylates myosin light chain (MLC) resulting in cross-bridge formation and muscle contraction. Pro-labour factors inhibit cAMPs production by activating the G-protein inhibitory receptor (Gi-R) on PM. Ca2+ signals are terminated by extrusion of Ca2+ from the cytosolic compartment or sequestration into internal stores via PM Ca2+ ATPases (PMCA) and SR Ca2+ ATPases (SERCA), respectively. Activation of Ca2+-sensitive K+ channels serves to repolarise the myocytes membrane and induces closure of VGCCs, limiting further Ca2+ entry. Dephosphorylation of MLC by MLC Phosphatase (MLCP) when specific GPCR activation stimulates RhoA-rho kinase results in resetting of the contractile system and relaxation at the level of the tissue. Nitric oxide binds to membranous Gq subunit of the GPCR resulting in increased cyclic guanosine monophosphate (cGMPs) levels which stimulates MLCP leading to smooth muscle relaxation (76).