Adaptation of the uterine arcade in rats to pregnancy

In order to study the adaptation of the uterine arterial system to pregnancy we measured vascular dimensions and other growth related data (DNA content and [3H]thymidine incorporation rate) on excised uterine arcades, pressurized to 100 mmHg, of rats before and during pregnancy (day 8, 18 and 21 of gestation). The vascular conductance of the arcade was calculated using a numerical method. In order to investigate the response of the arcade to flow impairment during early pregnancy, the same measurements were repeated on uterine arcades from pregnant animals (day 21 of gestation), where the left uterine artery had been ligated on day 8 of pregnancy. In adult virgin rats, the uterine arcade was 0.3 +/- 0.05 mm wide and 50 +/- 5 mm long. With these vascular dimensions the vascular conductance of the arcade (2.5 microliters/(s x mmHg] was calculated to be inadequate for the blood supply to the pregnant uterus at term. During the course of pregnancy modest changes were seen: The arcade increased 80% in length, 30% and 80% in internal diameter at the ovarian and cervical origin respectively and 6 times in conductance. Weight of the arcades increased 2-3-fold, [3H]thymidine incorporation rate 7-fold whereas the DNA mass remained constant. Ligation of the uterine artery on day 8 caused a 2 times increase in internal diameter of the ovarian (open) origin of the arcade without change in weight, whilst the cervical (ligated) origin of the arcade had the same internal diameter as that of the control group. The calculated vascular conductance of the ligated arcade was the same as for controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abortion in mice with excessive erythrocytosis is due to impaired arteriogenesis of the uterine arcade

We postulate that repeated pregnancy loss, intrauterine growth restriction, and preeclampsia are caused by impaired elevation of uterine blood flow due to disturbed arteriogenesis of the uterine arcade. This hypothesis is based on the observation that pregnant human erythropoietin-overexpressing (plasma levels elevated 12-fold) mice (termed tg6 mice) suffering from excessive erythrocytosis generally abort at midgestation unless their hematocrit of 0.85 is drastically lowered. Transgenic mice show placental malformations that parallel those observed in pregnant women suffering from impaired uterine perfusion. Shear stress, a key factor inducing arteriogenesis, was 5-fold lower in tg6 mice compared with wildtype (WT) littermates. Consequently, uterine artery growth was reduced, and dramatically fewer viable pups (1.63 +/- 2.20 vs. 8.10 +/- 0.74 in WT) of lower weight (1.29 +/- 0.07 g vs. 1.62 +/- 0.12 g in WT) were delivered in first pregnancies. Only in subsequent pregnancies did tg6 deliver approximately the expected number of pups. Birth weights of tg6 offspring, however, remained reduced. As the spleen is a major site of extramedullary erythropoiesis in tg6 animals, splenectomy reduced the hematocrit to 0.6-0.7. In turn, shear stress increased to normal values, and splenectomized primiparous tg6 showed normal uterine artery growth and delivery of pups similar in number and weight compared with WT. We conclude that poor arteriogenesis is a previously unappreciated cause for clinically important pregnancy complications.     

Comparative characteristics of villous chorionic polysaccharides during the first 3 months of human uterine and tubal pregnancy]

Qualitative composition of polysaccharides has been studied in 100 chorions of human fetuses, 3.5--12 weeks of embryonic development, 40 of them have been obtained from tubal pregnansies. It has been stated that in villous stroma of the tubal pregnancy at the 4--5th week of gestation, sulphate polysaccharides appear that demonstrates an earlier maturation of villi at this type of pregnancy. It is possible that in the formation of intracellular substance of the villous stroma together with fibroblasts Kastschenko -- Hoffbauer's cells also participate. A characteristic feature for the tubal pregnancy is the appearance of distrophically changed villi beginning from the 4th week of gestation. In plasmodiotrophoblast of such villi the amount of Hale-positive and PAS-positive substances is sharply decreasing, and neutral polysaccharides, chondroitin-4-sulfate, chondroitin-6-sulfate and dermatan-sulfate (small amount) are intensively accumulating in the stroma.     

Ultrasound diagnostic schema for the determination of increased risk for chromosomal fetal aneuploidies in the first half of pregnancy

The aim of the study was to develop an early ultrasound diagnostic schema for the determination of increased risk for fetal chromosomal aneuploidies. The study was conducted on a population of 1318 pregnant women divided into 2 groups: 1255 women with the normal course of pregnancy and 63 women with diagnosed fetal abnormalities. There were 34 cases of chromosomal abnormalities (trisomy 21, 18, 13; triploidy; unbalanced inversion 9; deletion 16) and 29 cases of structural malformations. The estimation of the range of normal values was performed for the nuchal translucency (NT) measurement between 11 and 13 weeks and the nasal bone length (NB) measurement between 12 and 20 week. The results obtained in the collective set of normal pregnancies constituted the basis for the calculation of the range of normal values. The measurements of NB and NT showed a linear value increase with the pregnancy course. The following test characteristics (correlation to CRL) were recorded: NB - sensitivity 60%, specificity 98%, positive predictive value (PPV+) 43%, negative predictive value (NPV-) 98.9%. For the assumption that the test outcome means the presence or absence of the nasal bone in the ultrasound scan the sensitivity was 40%, but specificity 100%; NT - sensitivity 63.6%, specificity 98.2%, PPV+ 38.9%, NPV - 98.2%; NT + NB - presents similar characteristic to the NB or NT alone - sensitivity 55.6%, specificity 98.6%, PPV+ 50%, NPV - 98.9%. The following test characteristics for chromosomal aberration markers (correlation to BPD) were observed: NB - sensitivity 68.4%, specificity 97.4%, PPV+ 56.5%, NPV - 98.4%; NT - sensitivity 73.9%, specificity 97.9%, PPV+ 54.8%, NPV- 99.2%; NT + NB - sensitivity 94.7%, specificity 98.9%, PPV+ 90%, NPV - 99.7%, respectively. The "genetic sonogram" protocol for the structural defect detection was analysed: sensitivity was 80%, specificity 100%, PPV+ 100%, NPV - 99.7%. It is concluded that the new biometric parameter--nasal bone length (NB) and the corrected one--nuchal translucency thickness (NT) are useful markers for fetal abnormalities, especially for chromosomal aberrations. High predictive values of the diagnostic schema for the detection of aneuploidies and structural defects indicate that its application in correlation with the biparietal diameter (BPD) is highly recommended. The proposed schema is an effective algorithm for prenatal diagnostics characterised by high prognostic values. The possible introduction of the schema could result in a decrease of the invasive procedure rates, which could minimise the rate of miscarriages as a complication of amniocenteses.     

Serum levels of the adipokine chemerin are increased in preeclampsia during and 6 months after pregnancy

Preeclampsia is a serious cardiovascular complication in pregnancy which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, chemerin was introduced as a novel adipokine inducing insulin resistance in vitro and in vivo. In the current study, we investigated serum concentrations of chemerin by ELISA in control and preeclampsia patients during pregnancy (Control: n=37, preeclampsia: n=37) and 6 months after delivery (Control: n=35, preeclampsia: n=36). Furthermore, the association between chemerin and markers of renal function, glucose and lipid metabolism, as well as inflammation was studied in pregnant patients. Median maternal chemerin concentrations were significantly elevated in preeclampsia patients (249.5 [range: 123.1-366.9] μg/l) as compared to controls (204.8 [138.5-280.8] μg/l) (p<0.001). Furthermore, chemerin serum levels positively correlated with blood pressure, creatinine, free fatty acids, cholesterol, triglycerides (TG), leptin, adiponectin, and C-reactive protein in univariate analyses. In multivariate analyses, TG and leptin remained independently associated with circulating chemerin. Interestingly, median chemerin concentrations 6 months after delivery remained significantly higher in former preeclampsia patients (196.0 [119.8-368.7] μg/l) as compared to controls (152.2 [102.8-216.4] μg/l). Taken together, maternal chemerin serum concentrations are significantly increased in preeclampsia during and after pregnancy. Furthermore, TG and leptin are independent predictors of circulating chemerin during pregnancy.     

Elevated ethnocentrism in the first trimester of pregnancy

Recent research employing a disease-threat model of the psychology of intergroup attitudes has provided preliminary support for a link between subjectively disease-salient emotional states and ethnocentric attitudes. Because the first trimester of pregnancy is a period of particular vulnerability to infection, pregnant women offer an opportunity to further test this association. We explored the expression of intergroup attitudes in a sample of pregnant women from the United States. Consistent with the predictions of the disease-threat model, results from our cross-sectional study indicate that favoritism toward the ingroup peaks during the first trimester of pregnancy and decreases during the second and third trimesters. We discuss this finding in light of the possible contributions of cultural and biological factors affecting ethnocentrism.     

Bmp2 is critical for the murine uterine decidual response

The process of implantation, necessary for all viviparous birth, consists of tightly regulated events, including apposition of the blastocyst, attachment to the uterine lumen, and differentiation of the uterine stroma. In rodents and primates the uterine stroma undergoes a process called decidualization. Decidualization, the process by which the uterine endometrial stroma proliferates and differentiates into large epithelioid decidual cells, is critical to the establishment of fetal-maternal communication and the progression of implantation. The role of bone morphogenetic protein 2 (Bmp2) in regulating the transformation of the uterine stroma during embryo implantation in the mouse was investigated by the conditional ablation of Bmp2 in the uterus using the (PR-cre) mouse. Bmp2 gene ablation was confirmed by real-time PCR analysis in the PR-cre; Bmp2fl/fl (termed Bmp2d/d) uterus. While littermate controls average 0.9 litter of 6.2+/-0.7 pups per month, Bmp2d/d females are completely infertile. Analysis of the infertility indicates that whereas embryo attachment is normal in the Bmp2d/d as in control mice, the uterine stroma is incapable of undergoing the decidual reaction to support further embryonic development. Recombinant human BMP2 can partially rescue the decidual response, suggesting that the observed phenotypes are not due to a developmental consequence of Bmp2 ablation. Microarray analysis demonstrates that ablation of Bmp2 leads to specific gene changes, including disruption of the Wnt signaling pathway, Progesterone receptor (PR) signaling, and the induction of prostaglandin synthase 2 (Ptgs2). Taken together, these data demonstrate that Bmp2 is a critical regulator of gene expression and function in the murine uterus.     

Interferon-gamma contributes to the normalcy of murine pregnancy.

Uterine natural killer (uNK) cells are transient, large, heavily granulated, maternal lymphocytes present on the mesometrial side of the pregnant mouse uterus. These cells contribute to normal implantation site development. Cytokine production, particularly interferon (IFN)-gamma, is a major function of most NK cell subsets. In this study, uNK cells were assessed for IFN-gamma production. Local concentrations of IFN-gamma were measured in the mesometrial regions of murine implantation sites between Days 6 and 16 of gestation. IFN-gamma was detected by ELISA at all days studied in a random-bred (CD1) and an inbred (BALB/c) strain of immune-competent mouse and in two immune-deficient strains, SCID (NK(+), T(-), B(-)) and tgepsilon26 (NK(-), T(-), B(+)). Concentrations of IFN-gamma per implantation site peaked at Day 10 of gestation in NK(+) strains but were low and relatively constant in NK(-) mice. To evaluate the functions of IFN-gamma at murine implantation sites, pregnancy was studied in homozygously mated IFN-gamma(-/-) and IFN-gammaRalpha(-/-) mice and their congenic controls. Primiparous but not multiparous IFN-gamma(-/-) mice experienced significant fetal loss. Primiparous IFN-gammaRalpha(-/-) carried full litters to term. Implantation site pathology was demonstrated in both strains of gene-deleted mice by light microscopy and ultrastructurally. This included elevated numbers of uNK cells that contained fewer and smaller granules and, after Day 10 of gestation, progressive necrosis and loss of decidua. The presence of a fetus able to produce IFN-gamma did not modify the phenotype of pregnant IFN-gamma(-/-) mice. This study indicates that during murine pregnancy, uNK cells are the main source of IFN-gamma on the mesometrial side of the uterus and that IFN-gamma contributes to normal health of the midgestational decidua. Furthermore, evidence is presented that IFN-gamma-producing cells exist in mesometrial regions of implantation sites that are neither NK nor T cells.     

Occlusion and reformation of the rat uterine lumen during pregnancy

Implantation sites were obtained from rats at various stages of pregnancy and were studied by light microscopy and scanning electron microscopy. Early in pregnancy the uterine luminal epithelium and the decidual cells in the implantation site formed an implantation chamber containing the conceptus. The epithelial cells lining the chamber and the mouth of the chamber degenerated, and the uterine lumen that was mesometrial to the conceptus was obliterated such that the uterine lumen became discontinuous, and the luminal epithelia of intersite areas were isolated. As the conceptus continued to grow, the decidua-conceptus unit bulged into the intersite areas and was partially covered by an epithelium that eventually became discontinuous and degenerated. Once this had occurred, the luminal epithelium of the intersite areas reestablished contact antimesometrial to the decidua-conceptus unit, and the uterine lumen was again continuous. However, the epithelium lining the lumen was not complete in the mesometrial region because of the vascular connections between the uterine stroma and the placenta. Factors influencing the restructuring of the uterine luminal epithelium were discussed.     

Lineage, maturity, and phenotype of uterine murine dendritic cells throughout gestation indicate a protective role in maintaining pregnancy

Dendritic cells (DCs) are known to play a major role in the induction, maintenance, and regulation of immune responses. Recently, DCs have been described to be present at the feto-maternal interface in human decidua. However, only limited information is available about DC presence, phenotype, and--more importantly--function throughout gestation. Thus, we analyzed local (uterine) and systemic (blood) DCs in a murine model. DBA/2J mated CBA/J females with vaginal plugs were separated and killed on Gestation Days (GDs) 1.5, 3.5, 5.5, 6.5, 7.5, 8.5, 10.5, 13.5, 15.5, or 17.5. Frequency of uterine and blood CD11c+ DC, phenotype (coexpression of CD8alpha and major histocompatibility complex class II [MHC II] antigens), and presence of intracellular cytokines (interleukins 12 and 10) were determined by flow cytometry. The morphology of DC in the pregnant uterus was evaluated by immunohistochemistry. In uterus, the relative number of CD11c+ cells increased from GD 5.5, reaching a plateau on GD 9.5 until GD 17.5, while a transient peak of systemic CD11c+ cells was found on GD 8.5 and 10.5. The vast majority of uterine DCs were CD8alpha- and thus, belonged to the myeloid lineage. Interestingly, a significant peak of lymphoid DC was present on GD 1.5 and 5.5. Further, significantly more intracellular interleukin 10 than interleukin 12 was present in CD11c+ cells. Interestingly, mature DCs (MHC II+) were diminished from GD 5.5 to 8.5. Characterization of CD11c+ cell kinetics in uterus and blood reveals variation of phenotype during pregnancy, pointing toward an eminent immunoregulatory role of DCs throughout gestation at the feto-maternal interface.     

Conceptus development, uterine response, blood gases and endocrine function of gilts exposed to increased ambient temperature during early pregnancy

Fifteen crossbred gilts were used to determine the influence of heat stress during Days 8 to 16 after onset of estrus on the development of conceptuses and uterine and endocrine functions. Ten gilts were bred 12 and 24 h after the onset of estrus (Day 0), and five gilts were nonbred controls. On Day 5, catheters were inserted into the uterine-ovarian vein (UV), saphenous artery (SA) and saphenous vein (SV) of each gilt. An electromagnetic blood flow transducer was implanted around the main uterine artery. Pregnant (n=5) and nonbred (n=5) control gilts were exposed to 21 +/- 1 degrees C, and pregnant heat-stressed gilts (n=5) were exposed to 37 +/- 1 degrees C for 12 h and 32 +/- 1 degrees C for 12 h daily during Days 8 through 16 after estrus. Treatment did not influence the partial pressure of oxygen (PO(2)) and of carbon dioxide (PCO(2)) in the UV, SA and SV blood. Uterine blood flow was not altered by heat stress. On Day 16, total wet weight of conceptuses was reduced in the gilts that were heat-stressed compared with conceptuses from control gilts. Incorporation of (3)H-leucine into macromolecules in vitro by conceptuses from the heat-stressed gilts was reduced compared with control gilts. Concentrations of 15-keto-13, 14-dihydro prostaglandin F(2alpha) (PGFM) in peripheral blood were greater than 1 ng/ml between Days 13 to 16 after estrus in 20% of the pregnant control gilts, 60% of the heat-stressed pregnant gilts, and 100% of the nonbred gilts. Concentrations of estradiol in the SA were affected by treatment. These results indicate that heat stress of gilts between Days 8 to 16 after estrus reduced the amount of conceptus tissue and altered concentrations of estradiol in the peripheral circulation, but uterine blood flow and PO(2) and PCO(2) in blood were not affected.