Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition.
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.
Fetalvero
Kristina M
KM
Department of Surgery, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA.
Zhang
Peisheng
P
Shyu
Maureen
M
Young
Benjamin T
BT
Hwa
John
J
Young
Roger C
RC
Martin
Kathleen A
KA
D000328:Adult; D018031:Connexin 43 / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D011464:Epoprostenol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D009215:Myometrium / Q000378:metabolism*; D010120:Oxytocics / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D036801:Parturition / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy / Q000187:drug effects / Q000502:physiology*; D044006:Receptors, Epoprostenol / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology*
D018031:Connexin 43; D010120:Oxytocics; D044006:Receptors, Epoprostenol; D010121:Oxytocin; D011464:Epoprostenol; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017868:Cyclic AMP-Dependent Protein Kinases