Cyclic mechanical stretching and interleukin-1alpha synergistically up-regulate prostacyclin secretion in cultured human uterine myometrial cells.

Prostacyclin (PGI2), a potent uterine smooth muscle relaxant, is postulated to be a major prostaglandin (PG) secreted from the human myometrium. PGI2 metabolite concentrations in the maternal plasma were reported to be elevated during pregnancy, especially during labor. Recently, we developed cultured human myometrial cells from pregnant women and reported that cyclic mechanical stretching mimicking labor increased PGI2 secretion from these cells by up-regulating PGI2 synthase promoter activities. Since elevation of cervical/vaginal interleukin-1alpha (IL-1alpha) concentrations is also a characteristic feature of delivery, and IL-1alpha is a known stimulator of PG synthesis, we investigated a possible synergistic effect of cyclic mechanical stretching and IL-1alpha on PGI2 production in cultured human myometrial cells. Treatment with IL-1alpha (10 ng/ml) significantly augmented (4- to 60-fold) the secretion of PGI2, prostaglandin E2 (PGE2), prostaglandin F2alpha (PGF2alpha) and thromboxane A2 (TXA2) from cultured human myometrial cells obtained from non-pregnant and pregnant women as well as in cultured human umbilical artery and cultured human coronary artery smooth muscle cells (p < 0.05 for all comparisons). However, labor-like cyclic mechanical stretching up-regulated IL-1alpha-augmented PGI2 secretion from myometrial cells obtained from non-pregnant and pregnant women 2.1- to 2.8-fold (p < 0.05 for all comparisons), but not PGE2, PGF2alpha nor TXA2. Moreover, such an augumentation of PGI2 secretion by cyclic mechanical stretching was not observed in cultured human umbilical artery nor in cultured human coronary artery smooth muscle cells. These results suggest that cyclic mechanical stretching by labor, in concert with IL-1alpha stimulation, contributes to the increase in myometrial PGI2 secretion during delivery.

Role of leptin in pregnancy--a review.

Leptin is an adipocyte-derived hormone that decreases food intake and body weight via its receptor in the hypothalamus. In rodents, it also modulates glucose metabolism by increasing insulin sensitivity. We previously reported that leptin is produced by human placental trophoblasts. We also revealed that leptin gene expression in the placenta was augmented in severe pre-eclampsia, and suggested that placental hypoxia may play a role in this augmentation. Maternal plasma leptin levels correlated well with mean blood pressure, but not with body mass index. Plasma leptin levels in pre-eclamptic women with IUGR were higher than those without IUGR (P< 0.05). We further examined the effects of hyperleptinemia on the course of pregnancy by using transgenic mice (Tg) overexpressing leptin. In pregnant Tg mice, food intake was significantly less than non-Tg, and the fetal body weights were reduced to approximately 70 per cent of those of non-Tg. Resistin is a novel adipocyte-derived hormone that decreases insulin sensitivity and increases plasma glucose concentration, thus contributing the development of obesity-related type II diabetes mellitus. We recently found that resistin gene is expressed in the human placenta as well as adipose tissue. In this review, possible roles of placental leptin and resistin are discussed.

Nitric oxide increases matrix metalloproteinase-1 production in human uterine cervical fibroblast cells.

Since uterine cervical ripening is an active biochemical process similar in part to an inflammatory reaction, nitric oxide (NO) has been proposed as a key mediator of this event. However, the mechanism by which NO modulates human cervical ripening has not been fully elucidated. In the present study we investigated the presence of NO synthases in human uterine cervix by immunohistochemistry and reverse transcriptase-polymerase chain reaction analysis. Furthermore, we examined the presence of NO-mediated regulation of matrix metalloproteinase-1 (MMP-1) production in cultured human uterine cervical fibroblast cells using enzyme-linked immunosorbent assay and Northern blot analysis. Endothelial and inducible NO synthases were detected in the form of mRNA and protein expression in pregnant uterine cervix. Interleukin-1alpha (IL-1alpha) increased the expression of inducible NO synthase mRNA in cultured human uterine cervical fibroblast cells. IL-1alpha also increased MMP-1 secretion from the cultured cervical fibroblast cells. This IL-1alpha-augmented MMP-1 secretion was partially but significantly blocked by an NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester. On the other hand, NO donors increased MMP-1 production in the cultured cervical fibroblast cells. These findings together suggest that NO contributes to the process of cervical ripening via enhancement of MMP-1 production, and that IL-1alpha increases MMP-1 secretion from cervical fibroblasts at least in part via NO synthesis.

Activity of platelet-activating-factor-acetylhydrolase and the nitric oxide metabolite level in the plasma of pregnant women who develop transient hypertension during later pregnancy.

It is reported that plasma platelet-activating-factor-acetylhydrolase (PAF-AH) is elevated in patients with essential hypertension. In this study, plasma PAF-AH activity was measured during pregnancy and after delivery to examine the relationship between plasma PAF-AH activity and the development of transient hypertension (TH) during pregnancy. Moreover, in order to examine the involvement of endothelial injury in TH, the plasma level of nitric oxide metabolite (NOx; NO2+NO3) was measured. The plasma PAF-AH activity in 51 pregnant women was consecutively measured in the 1st, 2nd and 3rd trimesters of gestation, and after delivery. Forty-one cases were normal pregnancies and 10 cases were complicated by TH later during pregnancy. The PAF-AH activity in the normal pregnancy group decreased in the 2nd trimester of gestation compared with the 1st trimester, but was elevated in the TH group. The incidence of elevation of PAF-AH in the TH group was significantly (7/10; 70.0%; P<0.01, Chi-squared test) higher than in the normal pregnancy group (9/41; 22.0%). The plasma NOx levels in the 2nd trimester were higher than those in the 1st trimester in both the normotensive and TH group (P<0.05 for both comparisons). The 51 patients were classified into two groups according to the change in the PAF-AH in the 2nd trimester: group A consisted of 35 patients whose PAF-AH activity did not increase, and group B consisted of 16 patients whose PAF-AH activity increased. The incidence of development of TH during later pregnancy in group B was significantly (7/16; 43.8%; P<0.01, Chi-squared test) higher than in group A (3/35; 8.6%). Hypertension developed after 36 weeks' gestation in all patients in the TH group. The results of the present study suggest that changes in PAF metabolism may relate to regulation of blood pressure in pregnant women whose pregnancy is complicated with TH, whereas NO metabolism does not differ between women with TH and those having a normal pregnancy.

Diffuse cystic change of a term placenta with a normal newborn.

We recently encountered a case of term placenta with a diffuse cystic lesion of the villi. A 19-year-old primipara at 36 weeks of gestation underwent cesarean section due to breech presentation with premature rupture of the membranes; she delivered a mature male baby of 2,502 g with an Apgar score of 9/9. The placenta was 940 g in weight and 29 x 20 x 3 cm in size, and macroscopically had multiple cystic lesions (3-8 mm in diameter) that resembled hydatidiform moles. However, histopathological examination revealed that the severe hydropic change was localized in the stem villi but not remarkable in the terminal chorionic villi. Moreover, abnormal proliferation of the trophoblast was not observed. However, the hypertrophic change was observed in the vascular wall of stem villi, in which hyperplasia of smooth muscle-like cells was present. The urinary hCG levels at 1 month and 2 months after delivery were less than 50 IU/l. These findings indicate that the multiple cystic lesions of the placenta in this case are essentially different from those of a trophoblastic disease, and that the diffuse cystic lesion of the villi might have been secondary to changes in the local circulation.