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

Nov 27, 2008The Journal of clinical investigation

Prostacyclin prepares pregnant uterine muscle for stronger contractions during childbirth

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Abstract

Activation of the prostacyclin receptor (IP) upregulated contractile proteins and connexin 43 in human myometrial tissue.

During myometrial activation, proteins that prepare smooth muscle for contraction are increased, enhancing responsiveness to contraction-inducing signals.
The upregulation of COX-2 leads to the production of prostaglandins that promote contractions.
Prostacyclin (PGI2), typically a relaxant, was shown to stimulate the expression of contractile proteins through cAMP/PKA signaling.
Enhanced contractile responses to oxytocin were observed in myometrial tissue strips when PGI2 receptor activation occurred.
The induction of contractile proteins was influenced by the concentration and exposure time to the PGI2 analog iloprost.

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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 (PGI2), a smooth muscle relaxant. However, here we have shown that activation of PGI2 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 PGI2 analog iloprost and was blocked by both RO3244794 and PKA knockdown. We therefore propose that PGI2-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.

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

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