cAMP signaling in the placenta: a pivotal determinant of trophoblast fate and pregnancy outcomes

Cyclic adenosine monophosphate (cAMP) signaling is a crucial pathway which regulates a myriad of physiological processes. cAMP is synthesized by adenylyl cyclases and then degraded by phosphodiesterases (PDEs). This intricate interplay of synthesis and degradation, often localized to specific subcellular compartments, tightly regulates cAMP signaling in a context-dependent manner, ensuring that the normal levels of cAMP needed for specific cellular processes are maintained within cells. The downstream actions of cAMP are mediated by effectors such as protein kinase A (PKA) and exchange proteins activated by cAMP (EPAC). At the feto-maternal interface, these actions ensure a proper timing and spatial regulation of trophoblast proliferation, survival and differentiation along the villous and extravillous pathways, leading to successful placental development and pregnancy progression. Disruptions in cAMP signaling result in mal-formed and dysfunctional placentas, thus causing pregnancy complications such as preeclampsia and fetal growth restriction. This suggests that cAMP modulation in the uterine environment right after embryo implantation is a potential therapeutic strategy to prevent abnormal placentation and the associated pregnancy disorders.