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BackgroundIn humans, trophoblast invasion, vascular remodeling and placental development are critical to determine the fate of pregnancy. Since guinea-pigs (GP) and humans share common pregnancy features including extensive trophoblast invasion, transformation of the uterine spiral arteries and a haemomonochorial placenta, the GP animal model was deemed suitable to extend our knowledge on the spatio-temporal immunoreactive expression of the vasodilator arpeptide of the renin-angiotensin system, angiotensin-(1–7) [Ang-(1–7)] and its main generating enzyme, angiotensin converting enzyme 2 (ACE2).MethodsUtero-placental units were collected in days 15, 20, 40 and 60 of a 64–67 day long pregnancy in 25 Pirbright GP. Ang-(1–7) and ACE2 expression in utero-placental units were evaluated by immunohistochemistry.ResultsAng-(1–7) and ACE2 were detected in the endothelium and syncytiotrophoblast of the labyrinthine placenta, interlobium, subplacenta, giant cells, syncytial sprouts, syncytial streamers, and myometrium throughout pregnancy. In late pregnancy, perivascular or intramural trophoblasts in spiral and mesometrial arteries expressed both factors. Immunoreactive Ang-(1–7) and ACE2 were present in decidua and in the vascular smooth muscle of spiral, myometrial and mesometrial arteries, which also express kallikrein (Kal), the bradykinin receptor 2 (B2R), vascular endothelial growth factor (VEGF) and its type 2 receptor (KDR), but no endothelial nitric oxide synthase (eNOS). In addition, the signal of Ang-(1–7) and ACE2 was especially remarkable in giant cells, which also show Kal, B2R. eNOS, VEGF and KDR.ConclusionsThe spatio-temporal expression of Ang-(1–7) and ACE2 in GP, similar to that of humans, supports a relevant evolutionary conserved function of Ang-(1–7) and ACE2 in decidualization, trophoblast invasion, vascular remodeling and placental flow regulation, as well as the validity of the GP model to understand the local adaptations of pregnancy. It also integrates Ang-(1–7) to the utero-placental vasodilatory network. However, its antiangiogenic effect may counterbalance the proangiogenic activity of some of the other vasodilator components.

Prophylaxis of thromboembolism with low molecular mass (LMM) heparin may offer several advantages over conventional heparin during pregnancy. Heparin-related side effects as osteoporosis, local allergy, thrombocytopenia and increase in liver enzymes may occur less frequently with LMM heparin. However, LMM heparins of different origins have to be considered as individual pharmaceutical compounds. This is of special clinical importance regarding a possible placental passage. We performed a randomized controlled study comparing the anti-factor Xa activities in plasma samples of 60 pregnant women undergoing delivery at term and in the umbilical cord vein of the newborn after subcutaneous administration of 5,000 IU unfractionated (UF) heparin or 1,500 activated partial thromboplastin time units LMM heparin or placebo. Injections were performed about 2 h prior to the delivery. Maternal and fetal blood samples were taken at the same time to assay heparin activity by the heptest coagulation assay and the S2222 chromogenic substrate method. LMM heparin was detected in all maternal plasma samples whereas UF heparin was measurable only in about one third of them. UF heparin as well as LMM heparin were not detectable in samples taken from the umbilical cord vein. The data demonstrate that neither UF nor the LMM heparin used in this study cross the placenta in relevant inhibitory activity towards factor Xa. This finding is in accordance with the previous experiences regarding the safe administration of other LMM heparins for prophylaxis of thromboembolism during pregnancy.

The endothelium is a multifunctional heterogeneous tissue playing a key role in the physiology of every organ. To accomplish this role the endothelium presents a phenotypic diversity that is early prompted during vascular development, allowing it to cope with specific requirements in a time- and site-specific manner. During the last decade several reports show that endothelial diversity is also present in the umbilico-placental vasculature, with differences between macro- and microvascular vessels as well as arterial and venous endothelium. This diversity is evidenced in vitro as a higher angiogenic capacity in the microcirculation; or disparity in the levels of several molecules that control endothelial function (i.e., receptor for growth factors, vasoactive mediators, and adhesion molecules) which frequently are differentially expressed between arterial and venous endothelium. Emerging evidence suggests that endothelial diversity would be prominently driven by epigenetic mechanisms which also control the basal expression of endothelial-specific genes. This review outlines evidence for endothelial diversity since early stages of vascular development and how this heterogeneity is expressed in the umbilico-placental vasculature. Furthermore a brief picture of epigenetic mechanisms and their role on endothelial physiology emphasizing new data on umbilical and placental endothelial cells is presented. Unraveling the role of epigenetic mechanisms on long term endothelial physiology and its functional diversity would contribute to develop more accurate therapeutic interventions. Altogether these data show that micro- versus macro-vascular, or artery versus vein comparisons are an oversimplification of the complexity occurring in the endothelium at different levels, and the necessity for the future research to establish the precise source of cells which are under study.

The effect of di-2-ethylhexyl phthalate (DEHP) on lipid metabolism was studied in liver and brain from fetal rats taken 3 days before parturition from dams receiving dietary DEHP during gestation. In fetuses from rats receiving 0.5% or 1.0% DEHP in a stock diet, the incorporation of 14C-acetate and labeled mevalonate (3H or 14C) into the C27 sterols, C30 sterols, and squalene fractions of brain tissue incubated in vitro was significantly reduced between the confidence limits P <0.05 to P <0.001. When liver from fetuses was incubated with labeled mevalonate, incorporation of label into the C27 sterol and C30 sterol fractions was significantly reduced as well (P <0.02 to P <0.001), whereas incorporation of labeled mevalonate into the squalene fraction was not significantly altered. The incorporation of 14C-acetate into total hepatic lipids of the fetal rats was also studied, and statistically significant reductions in incorporation were observed in the lanosterol fraction (P <0.001), the combined fraction of sterol esters + squalene (P <0.02), and the combined fraction of cholesterol + diglycerides (P <0.01). No significant changes were observed in the incorporation of 14C-acetate into phospholipids, free fatty acids, or triglycerides. In 8-day old suckling rats delivered from dams fed 0.5% DEHP for the last 16 days of gestation and maintained on the same diet during the nursing period, the incorporation of 14C-mevalonate into hepatic C27 sterols, in vitro, was significantly depressed (P <0.05) whereas in corporation into C30 sterols and squalene was similar to control values. In these same suckling rats, body weights were significantly lower in the control group (21.7 vs. 18.8 g, P <0.01), whereas liver weight as a % of body weight was significantly higher (P <0.01) in rats nursing from the DEHP-fed dams. The results ind'teate that the inhibitory effect of dietary DEHP on lipid metabolism in the mature rat is transmitted across the placental barrier to the developing fetus and that the abnormal pattern of lipid metabolism in rats delivered from DEHP-fed females is only partially restored to normal during the suckling periods.