Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition

Abstract

An incomplete understanding of the molecular events that regulate the myometrial transition from the quiescent pregnant state to the active contractile state during labor has hindered the development of improved therapies for preterm labor. During myometrial activation, proteins that prime the smooth muscle for contraction are upregulated, allowing maximal responsiveness to contractile agonists and thereby producing strong phasic contractions. Upregulation of one such protein, COX-2, generates PGs that induce contractions. Intriguingly, the predominant myometrial PG produced just prior to labor is prostacyclin (PGI 2 ), a smooth muscle relaxant. However, here we have shown that activation of PGI 2 receptor (IP) upregulated the expression of several contractile proteins and the gap junction protein connexin 43 through cAMP/PKA signaling in human myometrial tissue in organ and cell culture. Functionally, these IP-dependent changes in gene expression promoted an enhanced contractile response to oxytocin in pregnant human myometrial tissue strips, which was inhibited by the IP antagonist RO3244794. Furthermore, contractile protein induction was dependent on the concentration and time of exposure to the PGI 2 analog iloprost and was blocked by both RO3244794 and PKA knockdown. We therefore propose that PGI 2 -mediated upregulation of contractile proteins and connexin 43 is a critical step in myometrial activation, allowing for a maximal contractile response. Our observations have important implications regarding activation of the myometrium prior to the onset of labor.

Possible dual roles for prostacyclin in human pregnancy and labor

“…Given the pleiotropic nature of such cAMP-mediated regulation, one wonders whether other receptor-coupled stimuli (e.g., β-adrenergic agonists, prostaglandin E2, etc.) or pharmacological agents (e.g., forskolin) will elicit the same outcomes as outlined here by Fetalvero et al (4). Similarly, the expression of a wide variety of proteins would be expected to be changed by procedures that raise cAMP, not just the few focused on in the current study.…”

“…Based on the data presented in their study, Fetalvero et al (4) speculate that that their observations have important implications with respect to our understanding of myometrial activation, and hence clinical trials of prostacyclin-based therapeutics in pregnancy are warranted because they may lead to better strategies to induce labor or prevent preterm labor (PTL). PTL is the most serious pregnancy complication in developed countries and an important precedent of chronic disability.…”

“…4 and references therein). The authors used organ-cultured human uterine tissue strips obtained from pregnant women undergoing Caesarean delivery prior to the onset of natural labor or passaged cells cultured from human uterine tissue.…”

Physiological roles of connexins in labour and lactation

“…Although PGF2a dose-dependently increased the uterine activation proteins, including CX43 (Xu et al 2013), the most highly expressed prostaglandin in human myometrium is PGI2 (Omini et al 1979), which is normally known as a smooth muscle relaxant (Taggart et al 2008). In the pregnant human myometrium at term, however, PGI2 mediates upregulation of CX43 and contractile proteins such as SM-MHC and a-SMA via activating PKA in human myometrial cells in vitro, resulting in an enhanced contractile response to oxytocin (Fetalvero et al 2008).…”

“…Research with women or using animal models has shown that prolonged administration of progesterone is able to prevent preterm birth (Norman et al 2011). Progesterone probably acts as an antiinflammatory hormone and prevents prostacyclin activation (Fetalvero et al 2008). Interfering with prostaglandin synthesis as a therapeutic treatment to arrest myometrial contraction was considered to be a promising approach, but there is little evidence that COX2 inhibitors could prevent preterm labour as shown by a recent Cochrane study (Khanprakob et al 2012).…”