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GC Smith, WX Wu, and PW Nathanielsz

The aim of this study was to determine whether expression of prostanoid receptor genes varied with gestational age or labour in the decidua and chorion of baboons. Tissues were obtained at the time of Caesarean hysterectomy in 15 baboons, 10 prior to the onset of labour in the last third of pregnancy and 5 in spontaneous labour at term. Expression of prostanoid receptor genes was determined using Northern blot analysis and the level of expression was related to each of three housekeeping genes. Expression of the genes encoding the EP(1) and FP receptor in decidua and the EP(4) receptor in chorion was lower with advancing gestational age. Expression of the EP(2) receptor gene was lower in labour in decidua, whereas expression of the IP receptor gene was higher in labour in both decidua (twofold) and chorion (fourfold). It is concluded that there is a complex pattern of change in expression of prostanoid receptor genes in chorion and decidua with advancing gestational age and in association with labour. It seems likely that direct effects of prostaglandins on the choriodecidua may have an important role in parturition in the primate.

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WX Wu, XH Ma, Q Zhang, and PW Nathanielsz

Our objective was to examine the topology-, gestation- and labor-related changes of estrogen receptor (ER)alpha, progesterone receptor (PR), oxytocin receptor (OTR) and thrombospondin-1 (TSP1) mRNA in pregnant baboon myometrium. ER alpha, PR, OTR and TSP1 mRNAs extracted from the lower uterine segment and fundal myometrium of pregnant baboons not in labor between 121 and 180 days of gestational age (n=9) and in established spontaneous labor between 164 and 193 days of gestational age (n=5) were analyzed by Northern blot. There were no topology-, gestation- or labor-related changes of ER alpha and PR mRNA in or between the lower uterine segment or/and the fundus. OTR mRNA was the same in the lower uterine segment and the fundus from baboons not in labor and non-labor fundal, but not lower uterine segment, myometrial OTR mRNA increased with gestation (R(2)=0.81, P<0.05). Fundal OTR mRNA rose significantly compared with the lower uterine segment during spontaneous labor. TSP1 mRNA increased significantly in both the fundus and lower uterine segment during labor. TSP1 mRNA in the lower uterine segment during spontaneous labor was higher than in the fundus during spontaneous labor. In conclusion, fundal and lower uterine segment ER alpha and PR mRNA remained unchanged in late gestation and spontaneous labor. The increased OTR mRNA may serve as a mechanism to increase uterine sensitivity to OT during late gestation. The higher fundal OTR mRNA compared with the lower uterine segment provides polarity which assists fetal expulsion by uterine contractions during labor. The significance of increased TSP1 mRNA during labor may relate to homeostasis and merits further study.

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WX Wu, GC Smith, J Rose, and PW Nathanielsz

The present study was designed to determine the effect of the spatial gradient from the cervix to the uterine fundus on the control of local prostaglandin H synthase (PGHS) 2 mRNA expression. We performed total cesarean hysterectomies during the last trimester in 12 pregnant baboons, 7 not in labor and 5 in labor, and examined PGHS2 mRNA expression throughout the uterus. PGHS2 mRNA abundance was quantified by in situ hybridization and northern blot analysis in the uterine fundus, lower uterine segment and the different segments of the cervix. Quantitative northern blot and in situ analysis demonstrated a gradient of PGHS2 mRNA expression, with the highest levels at the level of the lower portion of the cervix and decreased expression through the mid- and upper portion of the cervix and lower uterine segment; the lowest levels of expression were seen in the uterine fundus. Moreover, cellular localization of PGHS2 mRNA and protein demonstrated high levels of expression in the cervical glandular epithelial cells with only occasional staining of smooth muscle cells in pregnant baboons. Decreased PGHS2 mRNA concentration gradient from the cervical external os to the fundus suggests that prostaglandin (PG) production in the uterus and cervix strongly depends on anatomical relations. This increased local PG production activity may be critical to pregnancy-associated lower uterine segment elongation, cervical softening and effacement in primate labor. These data provide a compelling biological basis for the use of PGHS2 inhibitors in the prophylaxis of preterm birth and cervical incompetence.

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WX Wu, XH Ma, Q Zhang, K Chakrabarty, and PW Nathanielsz

In the present study we characterized two labor-induced genes, DSCR1 (Down syndrome candidate region 1) and TCTE1L (murine t-complex like), which were identified by suppression subtractive hybridization in the pregnant ovine myometrium. DSCR1 and TCTE1L cDNA sequences were retrieved from a custom-made labor-myometrial cDNA library by hybridization screening. The characterized cDNA sequences include 5'-untranslated region (UTR), coding region and 3'-UTR, which are 12 bp, 351 bp and 1716 bp for TCTE1L, and 64 bp, 594 bp and 1539 bp for DSCR1 respectively. The two cDNA sequences encode proteins of 116 and 197 amino acids for TCTE1L and DSCR1 respectively. Northern analysis further confirmed the significant increases of myometrial DSCR1 and TCTE1L mRNA associated with spontaneous term labor (n=6) compared with gestation-matched controls not in labor (n=6). The abundance of DSCR1 and TCTE1L mRNA was attenuated when myometrial contraction was inhibited by Nimesulide (n=6), a specific prostaglandin H synthase 2 inhibitor. Fetal occupancy greatly upregulated DSCR1 and TCTE1L mRNA in the gravid horn during betamethasone-induced premature labor (n=6) compared with the non-gravid horn not in labor (n=3). Estradiol upregulated TCTE1L mRNA, but had no effect on DSCR1 mRNA expression in the non-pregnant sheep myometrium. Progesterone alone had no effect on both DSCR1 and TCTE1L mRNA expression, however progesterone antagonized estradiol's stimulating effect on myometrial TCTE1L mRNA expression in ovariectomized non-pregnant sheep. Upregulation of DSCR1 and TCTE1L in both betamethasone-induced premature labor and spontaneous term labor and inhibition of their expression by Nimesulide suggest a functional role of these two genes in myometrial activation associated with onset of labor. Mechanical stretch, labor and steroids differentially regulated DSCR1 and TCTE1L mRNA in the pregnant and non-pregnant sheep myometrium.