Browsing by Author "Liwa, Anthony Cuthbert"

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    The Spatial-temporal Contribution of Prostaglandin E2 Pathway to Rat Myometrial Contractile Function during Pregnancy and Labour
    (2020-09-24) Liwa, Anthony Cuthbert; Slater, Donna M.; Cole, William C.; Davidge, Sandra Thomas; Macdonald, Justin Anthony; Giembycz, Mark A.; Roth, Sheldon H.
    A key function of the uterus during pregnancy is to accommodate the growing fetus in a relatively quiescent environment. Towards the end of pregnancy, the uterus transforms to an active organ capable of generating forceful contractions during labour. Prostaglandins are thought to play a key role in the parturition process, with prostaglandin E2 (PGE2) being produced by uterine tissues, and having possible roles including stimulation of cervical ripening and uterine contractions. PGE2 exhibits diverse physiological actions, most probably depending on expression levels of selective PGE2 (EP) receptor subtypes; in the uterus EP1 and EP3 receptors may stimulate myometrial contraction, whereas EP2 and EP4 receptors may evoke relaxation. There is no consensus concerning their relative importance in regulating uterine function, and whether there are spatial- and/or time-dependent alterations in how PGE2 regulates uterine contractility via changes in PGE2 synthesis and/or EP receptor expression. We have hypothesised that, in myometrial tissue, expression of enzymes involved in PGE2 synthesis and/or the four EP receptors are regulated to provide for region- and time-dependent variations in the contribution of PGE2 to uterine quiescence in pregnancy and contractility in labour. An in vitro tissue bath was utilised to examine myometrial contractility responses to PGE2 and EP antagonists. Real-time polymerase chain reaction and western blotting experiments were used to determine expression of key enzymes involved in PGE2 synthesis plus the EP receptors. Uterine tissues from upper and lower uterine tissues at days 15-21 of gestation and during labour were used for the experiments. Our findings demonstrate the presence of spontaneous contractions in ex vivo uterine tissues at all time points studied. No regional difference in the magnitude of uterine contraction was observed with the exception of upper day 21, in which contractility was greater than in the upper compared to the lower uterus. The addition of PGE2 increased the spontaneous contractions in non-pregnant and day 15-21 pregnant tissues, but not those from rats in active labour. EP3 antagonist (L-798106) did not alter the actions of PGE2, whereas PGE2-evoked contractions of day 18 pregnant, but not in labour myometrium, were enhanced in the presence of EP4 antagonist (ONO-AE3-208). No significant differences in the expression of PGE2 isoenzyme and EP receptor mRNA and protein expression were detected in upper or lower uterine tissues during pregnancy and labour, with the exception of increased COX1 and decreased EP3 mRNA levels in tissues from rats in labour. These results suggest that rat uterine tissues can synthesize PGE2 throughout pregnancy and parturition but based on assessment of its effect on contractility in vitro, PGE2 only stimulates myometrial contractility during gestation and not in labour. PGE2 may therefore play a role in enhancing contractility of non-labour myometrium, but perhaps not in the regulation of myometrial contractility during labour. Alterations in the expression of PGE2 synthesizing enzymes and EP receptors would not appear to be the primary determinant of uterine tissue responsiveness. Furthermore, our results do not support the concept of functional regionality in terms of response to PGE2 of the rat uterus. The exact mechanisms of PGE2 regulation of uterine contractility await further investigation.