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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).