Novel regulation of pregnant human myometrial smooth muscle cell gap junctions by human chorionic gonadotropin.
Human myometrium contains hCG/LH receptors. There are fewer of these receptors during labor compared to no labor at preterm or term deliveries. Exogenous hCG can directly inhibit oxytocin-stimulated human myometrial contractions. These findings suggest that hCG may directly maintain myometrial quiescence during pregnancy. As maintenance of uterine quiescence may involve down-regulation of myometrial gap junctions, we investigated the effect of hCG on connexin-43 (CX-43) gene expression from RNA to protein and morphological gap junctions. The addition of 5 or 10 nM highly purified hCG to subconfluent cultures of pregnant myometrial smooth muscle cells resulted in a significant decrease in CX-43 protein levels. Higher hCG concentrations (100 and 1000 nM), however, had no effect. The maximal effect of hCG was seen at 4-8 h of culture, followed by recovery after a longer duration of culture. hCG treatment also concomitantly decreased CX-43 messenger RNA and morphological gap junctions. The hCG effect on CX-43 protein levels is hormone specific and mediated by protein kinase-A signaling. Estradiol and oxytocin increased, whereas progesterone decreased, CX-43 protein levels and morphological gap junctions. The oxytocin-induced increase was reversed by cotreatment with hCG. Although RU 486 alone had no effect on CX-43 protein levels, it prevented the down-regulating action of hCG and progesterone. In summary, our results demonstrate that hCG can directly decrease CX-43 messenger RNA, protein, and morphological gap junctions in cultured pregnant human myometrial smooth muscle cells. The hCG action is concentration and time dependent, hormone specific, and mediated by protein kinase-A signaling and appears to involve progesterone receptors. These data lend support to the concept that hCG could be one of the hormones responsible for maintaining uterine quiescence by down-regulating myometrial gap junctions during pregnancy.
Ambrus
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Department of Obstetrics and Gynecology, University of Louisville School of Medicine, Kentucky 40292.
Rao
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CV
D000911:Antibodies, Monoclonal; D006063:Chorionic Gonadotropin / Q000502:physiology*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D005260:Female; D017629:Gap Junctions / Q000502:physiology*; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D007986:Luteinizing Hormone / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009130:Muscle, Smooth / Q000502:physiology* / Q000648:ultrastructure; D009215:Myometrium / Q000502:physiology* / Q000648:ultrastructure; D011247:Pregnancy; D012333:RNA, Messenger; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D006063:Chorionic Gonadotropin; D018031:Connexin 43; D006728:Hormones; D012333:RNA, Messenger; D015735:Mifepristone; D007986:Luteinizing Hormone