Tanshinone IIA increased amniotic fluid volume through down-regulating placental AQPs expression via inhibiting the activity of GSK-3ß.

The mechanism of idiopathic oligohydramnios is still uncertain, and there is no effective and targeted treatment for it. Placental aquaporins (AQPs) were associated with idiopathic oligohydramnios. This study aimed to investigate the effect of tanshinone IIA on amniotic fluid volume (AFV) and its underlying molecular mechanisms related to placental AQPs (AQP1, AQP3, AQP8, AQP9). Results showed that compared with the women with normal AFV, placental AQP1, AQP3, AQP8, and AQP9 protein expressions were decreased in women with idiopathic oligohydramnios. Immunohistochemistry revealed localization of AQP1, AQP3, AQP8, and AQP9 mainly in trophoblast cells within labyrinth zone of mouse placenta. Also, AQP1 was located in fetal vascular endothelial cells. Pregnant mice were administered with tanshinone IIA (10 mg/kg or 50 mg/kg, n = 8, respectively) or vehicle (n = 8) from 9.5 to 18.5 gestational day (GD). Tanshinone IIA markedly increased the AFV in pregnant mice, without the effects on embryo numbers per litter, atrophic embryo rate, fetal weight, and placental weight, as well as increased the expressions of AQPs and inhibited the activity of GSK-3ß in mice placenta. In JEG-3 cells, tanshinone IIA downregulated AQP1, AQP3, AQP8, AQP9 expressions and inhibited the activity of GSK-3ß. Activating GSK-3ß with MK-2206 eliminated these alterations. Thus, tanshinone IIA could increase AFV in pregnant mice, possibly through downregulating placental AQP1, AQP3, AQP8, and AQP9 expression via inhibiting the activity of GSK-3ß. Tanshinone IIA may be optional for the treatment of idiopathic oligohydramnios.

Correlation of amniotic fluid index and placental aquaporin 1 levels in terms of preeclampsia.

INTRODUCTION: Aquaporin 1 (AQP1) plays an important role in regulation of maternal-fetal fluid exchange and amniotic fluid volume. This present study aimed to determine the relationship between amniotic fluid index and placental AQP1 levels in terms of preeclampsia, and to reveal possible pathophysiological changes of AQP1 expression under preeclamptic conditions. METHODS: Placental tissues and medical records information were obtained from 389 preeclamptic and 447 uncomplicated pregnancies. Placental AQP1 levels were analyzed by molecular biological methods, DNA methylation within gene promotor was determined by targeted bisulfite sequencing assay. RESULTS: Here, we found that preeclamptic pregnancy had a greater frequency of oligohydramnios, and higher placental AQP1 levels. There was a significantly inverse correlation between amniotic fluid index and placental AQP1 levels in preeclampsia cases. Additionally, the increased AQP1 was correlated with a decreased DNA methylation within its gene promoter. DISCUSSION: Overall, this was the first description that a greater frequency of oligohydramnios in preeclampsia was strongly associated with reprogrammed AQP1 expression via a DNA methylation-mediated epigenetic mechanism. This study suggested AQP1 might play an important role in regulating maternal-fetal fluid balance under preeclamptic conditions, providing new information for further understanding the pathophysiological mechanism of oligohydramnios in preeclampsia.

Histological distribution pattern of hemosiderin deposition on the chorionic plate and fetal membrane of diffuse chorioamniotic hemosiderosis related to chronic abruption oligohydramnios sequence.

INTRODUCTION: Chronic abruption oligohydramnios sequence (CAOS) is histologically characterized by diffuse chorioamniotic hemosiderosis (DCH). However, the criteria for the histological evaluation of the extent of CAOS-related hemosiderin deposition (HD) of the membranes and the difference in HD between the chorionic plate (CP) and fetal membrane (FM) are not well studied. This case control study compared the degree and distribution pattern of HD on CP and FM to present the histological features of DCH and the criteria for histological evaluation. METHODS: From the medical records of Kyoto University Hospital (2010-2019), we selected 20 CAOS cases that were clinically diagnosed by Elliot's criteria. Twenty non-CAOS cases matched to the CAOS group by gestational age were selected as controls. We compared the clinical data and pathological features in the two groups. We performed iron staining in all the cases and analyzed HD in CP and FM according to the histological score (H-Score: 0-12), which was determined as the density (0-3) multiplied by the extent of staining (0-4). RESULTS: HD was found in 100% (20/20) of CAOS and 15% (3/20) of control cases. In both the FM and CP, CAOS cases showed a significantly higher HS than control cases (CAOS, HS = 4-12; Control, HS = 0-1, p < 0.0001). Three CAOS patients presented HD alone in the CP. The HS of the CP was significantly higher than that of the FM (p = 0.0003). DISCUSSION: CAOS presented DCH with HS ≥ 4. This study showed that the CP might be more suitable for evaluating DCH than the FM.

Altered proteomics profile in the amnion of patients with oligohydramnios.

In pregnancy, idiopathic oligohydramnios is an obstetrical complication that compromises maternal health with poor perinatal outcome. Effective therapeutic treatment of this condition has been hampered by the unknown etiology and lack of understanding of cellular and molecular mechanisms that underlie idiopathic oligohydramnios. Amniotic fluid volume (AFV) is determined by intramembranous (IM) transport of amniotic fluid across the amnion and this pathway is regulated to maintain AFV within the normal range. To gain understanding of the causes of idiopathic oligohydramnios, we performed proteomics analysis of the human amnion to investigate the changes in protein expression profiles of cellular transport pathways and regulators in patients with oligohydramnios. Placental amnions from five patients with normal pregnancies and five patients with oligohydramnios were subjected to proteomics experiments followed by bioinformatics analysis. Using Ingenuity Pathway Analysis (IPA) software, five categories of biological functions and multiple canonical pathways within each category were revealed. The top differentially expressed proteins that participate in mediating these pathways were identified. The functional pathways activated include: (a) cellular assembly and organization, (b) cell signaling and energy metabolism, and (c) immunological, infectious, and inflammatory functions. Furthermore, the analysis identified the category of pathways that facilitate molecular endocytosis and vesicular uptake. Under oligohydramniotic conditions, the mediators of clathrin vesicle-mediated uptake and transport as well as intracellular trafficking mediators were up-regulated. These findings suggest that idiopathic oligohydramnios may be associated with alternations in cellular organization and immunological functions as well as increases in activity of vesicular transport pathways across the amnion.

CD15 as a marker of fetoplacental endothelial immaturity in IUGR placentas.

BACKGROUND: Structural or functional defects in the placenta, are the primary cause of growth restriction of the fetus. Morphological examination of such placentas from intrauterine growth restricted (IUGR) fetuses often appears deceptively normal. Evaluation of angiogenesis and fetoplacental vasculature is critical to understand the underlying pathogenesis of fetal growth restriction in both idiopathic as well as cases where it is thought to be secondary to complications like preeclampsia (PE). We analyzed the immaturity of fetoplacental vasculature using CD15, which is a stage specific embryonic antigen known to be expressed in immature endothelium. MATERIAL AND METHODS: One hundred and twelve placentas (81 from IUGR and 31 from gestationally appropriate samples (appropriate for gestational age (AGA)) were collected based on stringent inclusion criteria, and subjected to detailed examination of morphology and microscopy along with immunostaining for CD15. IUGR placentas known to have villous immaturity such as those associated with gestational diabetes, Rh negative pregnancies and anemia were excluded. The time of clinical onset of IUGR, associated complications like PE and oligohydramnios along with clinical variables were recorded. CD15 expression was scored in both distal and proximal vasculature and the values in IUGR and AGA pregnancies were compared and correlated with clinical variables. RESULTS: The mean CD 15 scores in both proximal vasculature (PV) as well as distal (DV) vasculature were significantly higher in the IUGR group compared to AGA (17.7 versus 5.16 in PV and 50.8 versus 23.7 in distal vasculature (DV)). Gestational age had no influence on CD15 staining in PV or DV in IUGR group, whereas preterm AGAs expressed higher CD15 only in the distal vessels. PE, oligohydramnios and the time of onset of IUGR did not influence the fetal vascular immaturity, as measured by CD15 scores. Although none of the clinical or obstetric factors influenced CD15 staining in AGA, fetal vessel immaturity in the IUGR group remained high even after adjusting for confounding variables like maternal age, gestational age and birth weight. Histological features suggestive of chronic hypoxia were significantly higher in IUGR placentas, compared to AGA and correlated positively with CD15 expression. CONCLUSION: Fetoplacental endothelium in both PV and DV is immature in IUGR irrespective of the gestational age or any other associated factors and CD15 immunodetection is a valuable marker for assessment of immaturity.

Danshen extract regulates the expression of aquaporin 3 in human amniotic epithelial cells.

Danshen extract has been used in the treatment of oligohydramnios, however, the mechanism of its action has not been elucidated. Previously, we demonstrated that down-regulation of AQP3 in fetal membranes may contribute to the development of oligohydramnios. In this study, we investigated the effects of Danshen extract on AQP3 expression in human amniotic epithelial cells from term pregnancies with oligohydramnios or those with those with (those with) normovolemic amniotic fluid. Human amniotic epithelial cells from the oligohydramnios group expressed a lower level of AQP3 mRNA and protein than those with normovolemia. Tweleve hour (Twelvehours) of treatment with Danshen extract, in a dose dependent manner, significantly increased the expression of AQP3 in the two groups. However, human amniotic epithelial cells from the oligohydramnios patients showed a greater sensitivity to the treatment of Danshen extract. These data provide a molecular basis for the treatment of patients with oligohydraminos.

Linking expression of aquaporin 3 to activation of JNK pathway.

Aquaporin 3 (AQP3) has been shown to be low in the amnion and chorion tissues of patients with oligohydramnios and that S. miltiorrhiza, a Chinese herbal medicine, results in increased AQP3 in human amniotic epithelial cells (hAECs). Here, we provide evidence for the involvement of the JNK pathway in AQP3 regulation in isolated oligohydramnios tissues in vitro, in hAECs derived from normal amniotic fluid and fluid from patients with isolated oligohydramnios. Phosphorylation of JNK was suppressed by pretreatment of cells with JNK-specific inhibitor (SP600125) and was up-regulated by S. miltiorrhiza; S. miltiorrhiza combined with SP600125 prevented SP600125-induced down-regulation of phospho-JNK both in normal amniotic fluid volume and in isolated oligohydramnios. In isolated oligohydramnios, AQP3 expression was significantly suppressed by SP600125 in a concentration- and time-dependent mannner, while its expression was up-regulated by S. miltiorrhiza. S. miltiorrhiza combined with SP600125 inhibited the increased expression of AQP3 relative to the S. miltiorrhiza treated group. Together, the data suggest that c-jun N-terminal kinase (JNK) pathway unerlies the regulation of AQP3 by S. miltiorrhiza amnion and chorion tissues.

Aquaporin 3 Expression Induced by Salvia Miltiorrhiza via ERK1/2 Signal Pathway in the Primary Human Amnion Epithelium Cells from Isolated Oligohydramnios.

Salvia miltiorrhiza is one of the most common Chinese herbal drugs, which is effective to treat oligohydramnios. In this study, the aim was to investigate how Salvia miltiorrhiza regulate aquaporin 3 expression in the human amnion epithelial cells (hAECs) with normal amniotic fluid volume or isolated oligohydramnios, whether via extracellular signal regulated kinase1/2 (ERK1/2) signal transduction pathway or not. Primary hAECs cultures from 120 patients were incubated with Salvia miltiorrhiza or/and ERK1/2 inhibitor-- U0126. Localization of aquaporin 3 was detected by immunohistochemistry and the expression of total ERK1/2, phospho-ERK1/2 (p-ERK1/2) and aquaporin 3 was detected by Western blot. The results were: (1) In hAECs with normal amniotic fluid volume, treatment with 10 µmol/L of U0126 for 6 h resulted in the optimal inhibition of p-ERK1/2 (P<0.05). However, the expression of total ERK1/2 or aquaporin 3 did not significantly change after different concentrations or time of U0126 treatment. Salvia miltiorrhiza significantly up-regulated aquaporin 3 expression, which was not affected by U0126. (2) In hAECs with isolated oligohydramnios, treatment with 5 µmol/L of U0126 for 2 h resulted in the optimal inhibition of p-ERK1/2 and the lowest expression of aquaporin 3 (P<0.05). Moreover, Salvia miltiorrhiza significantly up-regulated aquaporin 3 expression, which was obviously blocked by U0126. These results suggest that Salvia miltiorrhiza may regulate aquaporin 3 expression in hAECs. In addition, in hAECs with isolated oligohydramnios, Salvia miltiorrhiza may regulate the expression of aquaporin 3 via the ERK1/2 signal transduction pathway, which provides a novel thread to the improved treatment for isolated oligohydramnios.

[PECULIARITIES OF THE COURSE OF PREGNANCY, THE IMPLICATIONS OF DELIVERY IN WOMEN WITH PREECLAMPSIA IN THE CONDITIONS OF NATURAL IODINE DEFICIENCY].

The level of preeclampsia in 2.2 times higher in mountain regions as compared with lowland. In the presence of concomitant pathology of the thyroid gland on a background of natural iodine deficiency in pregnancy complicated with recurrent pregnancy loss in 2.8 times more primary placental insufficiency in 3.6 times, oligohydramnios 1.5 times, premature rupture of the amniotic fluid in 1.9 times, anemia, preeclampsia develops at earlier periods of gestation and more difficult to correct medication, in most cases becomes more severe.

Expression and localization of aquaporins 8 and 9 in term placenta with oligohydramnios.

To test the expression and localization of aquaporins 8 (AQP8) and 9 (AQP9) in human term fetal membranes and placenta in both oligohydramnios and normal amniotic fluid volume (AFV) groups and to explore the association between aquaporin expression and oligohydramnios. Real-time polymerase chain reaction and immunohistochemistry were used to determine AQP8 and AQP9 expression levels and localization in amnion, chorion, and placenta, respectively. In addition, compared with the normal AFV group, the expression levels of both AQP8 and AQP9 in amnion in oligohydramnios group were significantly decreased, while their expressions in placenta were significantly increased. The expression level of AQP9 was also significantly decreased in chorion, while that of AQP8 was unchanged. Both AQP8 and AQP9 may play an important role in water flow both in intramembranous absorption and in placental water transfer. Our study offers the potential therapeutic approach for oligohydramnios.

The expression and regulation of aquaporins in placenta and fetal membranes.

Previous studies by our group as well as other researchers have found expression of Aquaporins (AQPs) 1, 3, 8, and 9 in human chorioamniotic membranes and placenta. Our previous study found that the alteration of the expression of AQPs 1, 3, 8, and 9 in placenta and fetal membranes was an adaptive response to maintain amniotic fluid homeostasis in case of abnormal amniotic fluid volume, which is likely to affect the intramembranous absorption and transport of water and solute from mother to fetus. However, the actual regulation mechanisms of intramembranous absorption and placental water flow are not yet clear, making it difficult to treat abnormal amniotic fluid volume effectively. Several studies found that many factors, including hormone levels, osmotic pressure, temperature, and oxygen concentration, regulate expression of AQPs in placenta, fetal membranes, and other mammalian organs through several signal transduction pathways, such as the cAMP, the MAPK, the PI3K/AKT, and the PKC pathways. These factors could provide potential therapeutic targets for the treatment of abnormal amniotic fluid volume.

Recurrent Johanson-Blizzard syndrome in a triplet pregnancy complicated by urethral obstruction sequence: a clinical, molecular, and immunohistochemical approach.

We report on a triplet pregnancy of consanguineous parents with one fetus being affected by recurrent Johanson-Blizzard syndrome (JBS). At autopsy in the 35th gestational week, the affected triplet presented with an especially severe and lethal manifestation of the disorder as compared to his elder affected brother and to cases in the literature, thus exemplifying great interfamilial and intrafamilial phenotypic variability. Arhinencephaly and cystic renal dysplasia associated with urethral obstruction sequence were features not described previously in the literature. In addition to the lack of exocrine acini as the characteristic feature of JBS, the pancreas revealed a resorptive inflammatory reaction with infiltration by eosinophilic granulocytes that focally dispersed onto islets of Langerhans, thus favoring a progressive destructive rather than primary dysplastic process and possibly explaining the occurrence of diabetes mellitus in later life. JBS maps to chromosome 15q15-q21.1 and is associated with mutations in the UBR1 gene. Testing the fetus and the affected sibling revealed a homozygous truncating mutation in UBR1. The resulting absence of the UBR1 protein was confirmed by Western blot. Immunohistochemical staining using a commercial anti-UBR1 antibody demonstrated staining, presumably artifactual. This finding suggests that, until an appropriately validated antibody has been identified, this modality should not be utilized for diagnosis or confirmation of this disorder.

[Implications of retinoid pathway in human fetal membranes: study of target genes]. / Étude de la voie des rétinoïdes au sein des membranes fœtales humaines: mise en évidence de gènes cibles.

Retinoids (active derivatives of vitamin A) were already demonstrated to be important morphogenes and their implication at the placental and fetal level was already established. A new field of research is now developed in order to show their role on fetal membranes constituted by amnion and chorion. To describe the role of retinoids on these membranes, our studies were focused on target gene research. Firstly, all metabolism enzymes needed to vitamin A pathways were demonstrated to be present and active in signal transduction. Secondly, a bioinformatic analysis was performed to assess a list of potential target genes that could be classified in different biological pathways (inflammation, retinoids, hormones, vascularization, extracellular matrix and water homeostasis). Then, it was demonstrated that the gene coding for PLAT, implied in the degradation of extracellular matrix during programmed or premature rupture of membranes, is regulated by retinoids in a two steps mechanism. Finally, preliminary data showed that some aquaporins, which control water transport across membranes, are expressed and regulated by retinoids in the fetal membranes. A disregulation in pathologies like oligo or poly-hydramnios can be anticipated. Improvement of our knowledge about the retinoid implications is a key point in order to obtain a precise and complete documented cartography of the vitamin A (regulating) in amniotic membranes (regulated) that will permit the development of new diagnostic and therapeutic strategies.

Early compensatory adaptations in maternal undernourished pregnancies in rats: role of the aquaporins.

OBJECTIVE: To investigate the effect of maternal undernutrition (MUN) during pregnancy on fetal and placental weight, amniotic fluid (AF) volume, AF osmolality and ion concentrations at gestational ages E16 and E20. We also quantified protein expression of water channels (aquaporins; AQPs). METHODS: Pregnant rat dams were fed an ad libitum diet (AdLib; n = 6) or were 50% MUN (n = 6) beginning at E10 of gestation. At E16 and E20, we assessed the effect of MUN on fetal and placental weights, AF volume and osmolality, and placental expression of AQP1, 8 and 9. We focused on two uterine positions (proximal and mid-horns) with the extremes of nutrient/oxygen supply. We also separately studied the basal zone (hormone production) and the labyrinth zone (feto-maternal exchange). RESULTS: We showed that at E16, MUN fetal, and placental weights were unchanged and that, similarly, MUN AF volume, osmolality were comparable to AdLib. At E20, however, MUN fetal and placental zonal weights were significantly decreased. Inversely, due to MUN, maternal and fetal plasma osmolality and Na+ concentrations were significantly increased. Further, MUN AF volume was significantly reduced, while AF osmolality and Na+ concentration were increased at E20. CONCLUSION: Placental basal zone showed variable changes in AQP expression unrelated to position in the uterus or the gestational age (and thus severity of the fetal/placental growth restriction). In the labyrinth zone, MUN placental AQP1 was significantly decreased, whereas AQP8 and 9 expressions were significantly increased at E16 and E20. Dysregulation of AQPs' expression prior to the occurrence of oligohydramnios may represent a compensatory mechanism under conditions of early MUN.

[Expression of aquaporin-1 in human oligohydramnios placenta and fetal membranes].

OBJECTIVE: To detect aquaporin-1 mRNA (AQP1) expression in human oligohydramnios placenta and fetal membranes. METHODS: Placenta and fetal membranes samples were obtained from 5 women with oligohydramnios and 5 with normal amniotic fluid volume. AQP-1 mRNA expression in the tissue samples was detected by semi-quantitative RT-PCR. RESULTS: The expression of AQP1 mRNA was significantly lower in oligohydramnios placenta than in normal pregnancy placenta at term (P<0.05), and also significantly lower in oligohydramnios fetal membranes than in normal fetal membranes at term (P<0.05). CONCLUSION: Alterations in AQP1 mRNA expressions in human placenta and fetal membranes may play an important role in the disorder of maternal-fetal fluid exchange and amniotic fluid volume.

[Correlation between oligohydramnios and abnormal expressions of TXA2, PGI2 and TXA2R in the umbilical arterial blood and placenta].

OBJECTIVE: To investigate the roles of thromboxane A(2) (TXA(2)) and prostaglandin I(2) (PGI(2)) in development of oligohydramnios. METHODS: The concentration of TXB(2) and 6-keto-PGF1 in umbilical cord blood collected from 30 normal parturients (control) and 30 parturients with oligohydramnios was detected by radioimmunoassay to calculate the TXA(2)/PGI(2) ratio. Immunohistochemistry was performed to detect the contents of TXA(2)R in vascular endothelial cell in the placental villi. RESULTS: Compared with the control group, the concentration of umbilical cord blood TXB(2) in oligohydramnios group was significantly increased (P<0.01), but the elevation of 6-keto-PGF(2) concentration was not statistically significant (P>0.05). The oligohydramnios group showed significantly higher positivity rates of TXB2 and 6-keto-PGF1 in than the control group (P<0.01), and the positivity rate of TXA(2)R in the vascular endothelial cells in the placental villi was also significantly higher in the oligohydramnios group (22/30, 77.3% vs 11/30, 36.7%, P<0.05). Most of the TXA(2)R-positive cases in the oligohydramnios group showed strong positivities of TXA(2)R. CONCLUSION: Abnormal elevation of TXA(2) concentration in the umbilical cord blood and the TXA(2)/PGI(2) imbalance are responsible for the development of oligohydramnios.

Expression of aquaporin 1 and aquaporin 3 in fetal membranes and placenta in human term pregnancies with oligohydramnios.

OBJECTIVE: To explore the pathophysiology of oligohydramnios, the association between the expression of aquaporin 1 and aquaporin 3 in fetal membranes and placenta and oligohydramnios was investigated. METHODS: Sixty patients underwent elective cesarean sections at term were studied, 30 patients with isolated oligohydramnios and the other 30 with normal amniotic fluid volume (AFV). Real-time polymerase chain reaction and immunohistochemistry were employed to determine expression and localization of aquaporin 1 and aquaporin 3 in amnion, chorion and placenta, respectively. RESULTS: The expression of aquaporin 1 and aquaporin 3 was detected in amnion, chorion and placenta using real-time RT-PCR. By immunohistochemistry, aquaporin 1 and aquaporin 3 protein expressions in amnion epithelia and chorion cytotrophoblasts were identified. In placenta, aquaporin 1 was detected in placental vessels, while aquaporin 3 was found in trophoblast cells. In comparison to normal AFV group, there was a significant decrease of aquaporin 1 expression in amnion in oligohydramnios group, but no significant difference in chorion and placenta between the two groups. The expression of the aquaporin 3 in amnion and chorion in oligohydramnios group was significantly decreased, while expression in placenta was significantly increased compared with that in normal AFV group. CONCLUSIONS: Alteration of aquaporin 1 and aquaporin 3 expression in fetal membranes and placenta may be important in the pathophysiology of isolated oligohydramnios.

Experimental oligohydramnios decreases collagen in hypoplastic fetal rat lungs.

Neonates with premature rupture of the membrane and oligohydramnios have an increased risk of acute respiratory morbidity. The aims of this study are to investigate the effects of experimental oligohydramnios on transforming growth factor (TGF)-beta1 and connective tissue growth factor (CTGF) expressions and collagen level in fetal rat lungs. On day 16 of gestation, we anesthetized timed pregnant Sprague-Dawley dams, punctured the uterine wall and fetal membranes of each amniotic sac which resulted in oligohydramnios. Fetuses in the opposite uterine horn served as controls. On days 19 and 21 of gestation, fetuses were delivered by cesarean section. Rats exposed to oligohydramnios exhibited significantly lower lung weight/body weight ratios on days 19 and 21 of gestation than did the control rats. Lung type I collagen and TGF-beta1 mRNA expressions and lung collagen levels were significantly decreased in rats exposed to oligohydramnios on days 19 and 21 of gestation. Type I collagen and inhibitors of metalloproteinase-1 (TIMP-1) proteins were decreased and matrix metalloproteinase-1 (MMP-1) was increased in oligohydramnios-exposed rats on days 19 and 21 of gestation. CTGF mRNA expressions were comparable between control and oligohydramnios-exposed rats on days 19 and 21 of gestation. These data suggest that downregulation of collagen might be involved in the pathogenesis of oligohydramnios-induced respiratory morbidity.

Retinoic acid fails to reverse oligohydramnios-induced pulmonary hypoplasia in fetal rats.

All-trans retinoic acid (ATRA) stimulates platelet-derived growth factor (PDGF)-A expression and enhances alveolarization in rat lungs. On d 16 of gestation, pregnant Sprague-Dawley rats were randomly assigned to either a retinoic acid group (intragastric ATRA at 10 mg/kg body weight) or a vehicle group. We punctured each amniotic sac, and fetuses in the opposite uterine horn served as controls. On d 21 of gestation, the fetuses were delivered by cesarean section. Rats subjected to oligohydramnios exhibited significantly lower lung weights and lung/body weight ratios, and ATRA had no effects on the body or lung weights of oligohydramnios-exposed rats. Lung PDGF-A and -B mRNA expression was significantly lower in oligohydramnios-exposed rats compared with control littermates of maternal vehicle-treated dams. Maternal retinoic acid treatment significantly increased PDGF-A and -B mRNA expression in control and oligohydramnios-exposed rats compared with all rats and oligohydramnios-exposed rats of maternal vehicle-treated dams, respectively. Rats exposed to oligohydramnios exhibited a significantly lower generation of alveolar saccules than did control rats in the maternal retinoic acid- and vehicle-treated groups. In this model, maternal retinoic acid treatment showed no positive effects on oligohydramnios-induced pulmonary hypoplasia in the pseudoglandular stage.

Oligohydramnios decreases platelet-derived growth factor expression in fetal rat lungs.

OBJECTIVE: To evaluate the effects of experimental oligohydramnios on lung growth, expression of platelet-derived growth factor (PDGF) and its receptors, and lung morphology in fetal rats. METHODS: On day 16 of gestation, we anesthetized timed pregnant Sprague-Dawley dams and punctured uterine wall and fetal membranes of each uterine sac which resulted in oligohydramnios. The fetuses in the opposite uterine horn served as controls. On days 19 and 21 of gestation, the fetuses were delivered by cesarean section and weighed, and the lungs were dissected free and weighed. RESULTS: Rats exposed to oligohydramnios exhibited significantly lower lung/body weight ratios on days 19 and 21 of gestation and significantly lower radial saccular counts on day 21 of gestation than did the control rats. Lung PDGF-A and PDGF-B gene and protein expression and elastin level were significantly decreased in rats exposed to oligohydramnios on days 19 and 21 of gestation. The PDGF receptor alpha and beta gene expression levels were significantly decreased in rats exposed to oligohydramnios on day 19 of gestation. CONCLUSION: A decreased PDGF expression may be important in the pathogenesis of oligohydramnios-induced pulmonary hypoplasia and suggests that supplementation may provide useful therapeutic strategies.