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 r eceptors during labor compared to no labor at preterm or term deliveri es. Exogenous hCG can directly inhibit oxytocin-stimulated human myome trial contractions. These findings suggest that hCG may directly maint ain 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 my ometrial smooth muscle cells resulted in a significant decrease in CX- 43 protein levels. Higher hCG concentrations (100 and 1000 nM), howeve r, had no effect. The maximal effect of hCG was seen at 4-8 h of cultu re, followed by recovery after a longer duration of culture. hCG treat ment also concomitantly decreased CX-43 messenger RNA and morphologica l gap junctions. The hCG effect on CX-43 protein levels is hormone spe cific and mediated by protein kinase-A signaling. Estradiol and oxytoc in increased, whereas progesterone decreased, CX-43 protein levels and morphological gap junctions. The oxytocin-induced increase was revers ed 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 directl y decrease CX-43 messenger RNA, protein, and morphological gap junctio ns in cultured pregnant human myometrial smooth muscle cells. The hCG action is concentration and time dependent, hormone specific, and medi ated by protein kinase-A signaling and appears to involve progesterone receptors. These data lend support to the concept that hCG could be o ne of the hormones responsible for maintaining uterine quiescence by d own-regulating myometrial gap junctions during pregnancy.