Possible dual roles for prostacyclin in human pregnancy and labor

Abstract

During pregnancy, the muscular layer of the uterine wall known as the myometrium, which is composed mainly of smooth muscle cells, is maintained in a state of relative quiescence. A switch from myometrial quiescence to myometrial activation is required to establish uterine contractions during labor. Researchers have long been perplexed by the fact that the major prostaglandin produced by the uterus just prior to labor, prostacyclin, is a smooth muscle relaxant. In this issue of the JCI, Fetalvero et al. provide data that they propose explains this paradox, at least in part (see the related article beginning on page 3966). The authors examined uterine tissue from pregnant women near term and found that prostacyclin stimulation, which raises cAMP levels that were previously thought to affect only myometrial quiescence, can promote myometrial activation over time by increasing the expression of a select group of proteins thought to be indicative of a uterine contractile state.

Figure 1. Possible pathways of prostacyclin-mediated stimulation of cAMP and myometrial activation.

Receptor-coupled G_αs stimulation of myometrial adenylyl cyclase (AC) activity raises intracellular cAMP levels. Prostacyclin, or hIP agonist iloprost, act via this route. cAMP is traditionally thought to set in operation a cascade involving activation of PKA bound to anchoring proteins (e.g., AKAP79), release of PKA catalytic subunits (C) from regulatory RIIβ subunits (R), and subsequent phosphorylation of intracellular proteins that effect myometrial relaxation and quiescence. An additional longer-term effect of G_αs-dependent cAMP elevation is promotion of the expression of genes encoding proteins with relaxant influences. Normally, G_αs stimulation of cAMP levels would alter gene expression via nuclear PKA (possibly bound to AKAP95) stimulation and subsequent activation of cAMP-dependent transcription factors, such as CREB and CREM. The report by Fetalvero et al. in this issue of the JCI (4) challenges the latter theory by suggesting that the G_αs-coupled receptor hIP actually induces, by raising cAMP levels, the positive transcription of genes encoding several proteins that are more associated with uterine activation prior to labor: SM2-MHC, h-caldesmon, α-SMA, calponin, and connexin 43 (Cx43). It remains to be determined whether hIP alteration of myometrial expression of these genes occurs via the cAMP-dependent transcription factors CREB and CREM. An alternative possibility may be for hIP (and other stimuli that raise cAMP levels) to activate another class of cAMP-responsive transducing molecules known as exchange proteins directly activated by cAMP (EPACs). Their role in human myometrium, and myometrial prostacyclin-dependent signaling pathways, remains to be resolved.