Molecular mechanisms of the interactions involving cyclic AMP in the myometrium during pregnancy

Preterm labour is the most important cause of perinatal mortality. Our ability to prevent preterm labour has been hindered by poor understanding of the factors that initiate human parturition. cAMP is a second messenger which plays significant role in respiratory, cardiovascular, and reproductive systems. The role of cAMP-signalling pathway in the maintenance of pregnancy has been investigated. My results suggest that during pregnancy, high cAMP levels repress OTR via PKA-dependent pathway and this repression may contribute to myometrial quiescence. My results also suggest that as pregnancy advances, the activity of cAMP/PKA pathway declines and, in contrast, the levels of Epac1, rise. This pattern may be associated with an increase in OTR expression, which may contribute to uterine contractions. The ability of cAMP to repress inflammation in human myometrial cells was explored. My results show that cAMP repress the expression of inflammation related genes and pro-inflammatory cytokines. These results suggest that high cAMP/PKA tone in pregnancy may exert an anti-inflammatory effect and a reduction of cAMP/PKA tone may contribute to the pro-inflammatory effects of labour. AKIP1 has been identified to act as a molecular switch, determining cAMP/PKA action towards NFκB activity in various cell types. To date, no study was done to investigate the role played by AKIP1 in myometrial cells. My results suggest that in myometrial cells, low AKIP1 levels, helps to promote the anti-inflammatory effects of cAMP/PKA. The ability of cAMP in enhancing myometrial response to progesterone was tested. The results suggest that cAMP enhanced progesterone responsive genes via PKA. Furthermore, the ability of progesterone to repress IL-1β-induced inflammation may be enhanced by cAMP. Knockdown studies using siRNA, suggest that cAMP acts via PKA to enhance the anti-inflammatory action of progesterone. Overall, these data support a novel role for cAMP which may help in the prevention of preterm labour.