Placental Vascular Development Research Articles

Maternal Supplementation Spermidine During Gestation Improves Placental Angiogenesis and Reproductive Performance of High Prolific Sows.

Spermidine (SPD) is a widely recognized polyamine compound found in mammalian cells and plays a key role in various cellular processes. We propose that SPD may enhance placental vascular development in pregnant sows, leading to increased birth weight of piglets. Six hundred and nine sows at 60 days of gestation were randomly assigned into a basal diet (CON group), basal diet supplemented 10 mg/kg of SPD (SPD1 group), and basal diet supplemented 20 mg/kg of SPD (SPD2 group), respectively. Compared with the CON, SPD1 significantly increased the average number of healthy piglets per litter and the placental efficiency (P < 0.05), while the average number of mummified fetus per litter and the percentage of weak piglets significantly decreased (P < 0.05). In the plasma metabolomics, SPD content in plasma of sows (P = 0.075) and umbilical cord plasma of piglets (P = 0.078) had an increasing trend in response to SPD1. Furthermore, SPD1 increased the expression of the vascular endothelial cell marker protein, platelet endothelial cell adhesionmolecule-1 (PECAM-1/CD31) and the density of placental stromal vessels (P < 0.05). Moreover, as compared to CON, SPD2 significantly decreased the average number of mummified fetus per litter (P < 0.05), while the placental efficiency and the expression of amino acid transporter solute carrier (SLC) family 7, member7 (SLC7A7) and glucose transporters SLC2A2) and SLC5A4 in placental tissue significantly increased (P < 0.05). These results suggest that maternal supplementation of SPD during pregnancy increased healthy litter number, and promoted placental tissue development. Our findings provide evidence that maternal SPD has the potential to improve the production performance of sows.

A Hypoxia-Decidual Macrophage Regulatory Axis in Normal Pregnancy and Spontaneous Miscarriage.

The significance of hypoxia at the maternal-fetal interface is proven to be self-explanatory in the context of pregnancy. During the first trimester, low oxygen conditions play a crucial role in processes such as angiogenesis, trophoblast invasion and differentiation, and immune regulation. Recently, there has been increasing research on decidual macrophages, which contribute to the maintenance of immune tolerance, placental and fetal vascular development, and spiral artery remodeling, to investigate the effects of hypoxia on their biological behaviors. On these grounds, this review describes the dynamic changes in oxygen levels at the maternal-fetal interface throughout gestation, summarizing current knowledge on how the hypoxic environment sustains a successful pregnancy by regulating retention, differentiation and efferocytosis of decidual macrophages. Additionally, we explore the relationship between spontaneous miscarriages and an abnormal hypoxia-macrophage axis, shedding light on the underlying mechanisms. However, further studies are essential to elucidate these pathways in greater detail and to develop targeted interventions that could improve pregnancy outcomes.

Maternal serum PlGF associates with 3D power doppler ultrasound markers of utero-placental vascular development in the first trimester: the rotterdam periconception cohort.

Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature. In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7-9-11weeks gestational age (GA). The uPVV was measured as a parameter of volumetric development and reported the vascular quantity in cm3. The uPVS was generated as a parameter of morphologic (branching) development and reported the number of end-, bifurcation- crossing-or vessel points and total vascular length. At 11weeks GA, maternal serum biomarkers suggested to reflect placental (vascular) development were assessed: placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression with adjustments was used to estimate associations between serum biomarkers and uPVV and uPVS trajectories. Serum PlGF was positively associated with uPVV and uPVS development (uPVV: β = 0.39, 95% CI = 0.15;0.64; bifurcation points: β = 4.64, 95% CI = 0.04;9.25; crossing points: β = 4.01, 95% CI = 0.65;7.37; total vascular length: β = 13.33, 95% CI = 3.09;23.58, all p-values < 0.05). sEng/PlGF ratio was negatively associated with uPVV and uPVS development. We observed no associations between sFlt-1, sEng or sFlt-1/PlGF ratio and uPVV and uPVS development. Higher first-trimester maternal serum PlGF concentration is associated with increased first-trimester utero-placental vascular development as reflected by uPVV and uPVS. Clinical trial registration number Dutch Trial Register NTR6854.

Dietary sodium sulphate supplementation during mid-to-late gestation improves placental angiogenesis, bile acid metabolism, and serum amino acid concentrations of sows

Sulphate plays a vital role in the growth and development of the foetus. Sodium sulphate (Na2SO4) is utilised as a dietary protein nutrient factor and helps replenish sulphur elements in livestock and poultry. Therefore, this study aimed to investigate the effects of Na2SO4 supplementation in mid to late pregnancy on bile acid metabolism, amino acid metabolism, placental vascular development and antioxidant capacity of sows. At day 1 of gestation (G1), a total of twenty-six primiparous sows were carefully chosen and randomised into two groups: (1) control group, (2) Na2SO4 group (1.40 g/kg). Blood samples and placentas from sows were collected to measure biochemistry parameters, antioxidant indexes, placental vascular density, and indicators related to bile acid metabolism and amino acid concentrations, respectively. We found that dietary supplementation with Na2SO4 had a tendency for a reduction of incidence of stillborn at farrowing. Further observation showed that sows supplemented with Na2SO4 had decreased total bile acid level in cord blood, and increased placental gene expression of sulphotransferase and organic anion transport peptide. Na2SO4 supplementation increased catalase and total superoxide dismutase activity in cord blood, decreased placental malondialdehyde content, and enhanced placental protein expression of Sirtuin 1. Moreover, Na2SO4 consumption resulted in increased vascular density of placental stroma and elevated amino acid levels in sows and cord blood. Furthermore, maternal Na2SO4 consumption reduced serum urea concentrations of sows and umbilical cord blood at G114. In addition, dietary supplementation with Na2SO4 activated the protein expression of the placental mechanistic target of rapamycin complex 1. Collectively, these findings indicated that maternal supplementation with Na2SO4 during mid-to-late gestation elevated foetal survival via improving placental angiogenesis, bile acid metabolism and amino acid utilisation.

Possible Role of Netrin-1/Deleted in Colorectal Cancer/Vascular Endothelial Growth Factor Signaling Pathway in the Pathogenesis of Placenta Accreta Spectrum: A Case-control Study.

Netrin-1, an epithelial-secreted protein, plays a key role in placental formation through the promotion of cytotrophoblast proliferation and placental vascular development. These effects are mediated through several receptors, including the deleted in colorectal cancer (DCC) receptor. Placenta accreta spectrum (PAS) is an exaggerated trophoblastic invasion into the uterine myometrium. The exact etiology is unknown, but it is believed that increased trophoblastic invasion, defect decidualization, and/or abnormal angiogenesis might play a role. Our study aimed to investigate the suggested role of macrophage-induced netrin-1/DCC/vascular endothelial growth factor (VEGF) signaling in PAS pathogenesis. A total of 29 women with PAS (as cases) and 29 women with normal pregnancies (as controls) were enrolled in the study. At delivery, placental tissues of both groups were collected and processed for the evaluation of placental netrin-1 level by enzyme-linked immunoassay technique and immunohistochemical analysis of tissue DCC receptor. Placental tissue netrin-1 level of PAS cases showed a statistically significantly higher value than those in the normal group. Significant overexpression of DCC receptors, VEGF, and enhanced macrophage recruitment was noted in PAS cases in comparison to the normal placenta. Macrophage-induced netrin-1/DCC/VEGF signaling might be involved in PAS pathogenesis through the enhancement of trophoblastic angiogenesis.

One-carbon metabolite supplementation to nutrient-restricted beef heifers affects placental vascularity during early pregnancy.

We hypothesized that restricted maternal nutrition and supplementation of one-carbon metabolites (OCM; methionine, folate, choline, and vitamin B12) would affect placental vascular development during early pregnancy. A total of 43 cows were bred, and 32 heifers successfully became pregnant with female calves, leading to the formation of four treatment groups: CON-OCM (n = 8), CON + OCM (n = 7), RES-OCM (n = 9), and RES + OCM (n = 8). The experimental design was a 2 × 2 factorial, with main factors of dietary intake affecting average daily gain: control (CON; 0.6kg/d ADG) and restricted (RES; -0.23kg/d ADG); and OCM supplementation (+OCM) in which the heifers were supplemented with rumen-protected methionine (7.4g/d) and choline (44.4g/d) and received weekly injections of 320mg of folate and 20mg of vitamin B12, or received no supplementation (-OCM; corn carrier and saline injections). Heifers were individually fed and randomly assigned to treatment at breeding (day 0). Placentomes were collected on day 63 of gestation (0.225 of gestation). Fluorescent staining with CD31 and CD34 combined with image analysis was used to determine the vascularity of the placenta. Images were analyzed for capillary area density (CAD) and capillary number density (CND). Areas evaluated included fetal placental cotyledon(COT), maternal placental caruncle (CAR), whole placentome (CAR + COT), intercotyledonary fetal membranes (ICOT, or chorioallantois), intercaruncular endometrium (ICAR), and endometrial glands (EG). Data were analyzed with the GLM procedure of SAS, with heifer as the experimental unit and significance at P ≤ 0.05 and a tendency at P > 0.05 and P < 0.10. Though no gain × OCM interactions existed (P ≥ 0.10), OCM supplementation increased (P = 0.01) CAD of EG, whereas nutrient restriction tended (P < 0.10) to increase CAD of ICOT and CND of COT. Additionally, there was a gain × OCM interaction (P < 0.05) for CAD within the placentome and ICAR, such that RES reduced and supplementation of RES with OCM restored CAD. These results indicate that maternal rate of gain and OCM supplementation affected placental vascularization (capillary area and number density), which could affect placental function and thus the efficiency of nutrient transfer to the fetus during early gestation.

Morphological evaluation of the feline placenta correlates with gene expression of vascular growth factors and receptors†.

Placental angiogenesis is critical for normal development. Angiogenic factors and their receptors are key regulators of this process. Dysregulated placental vascular development is associated with pregnancy complications. Despite their importance, vascular growth factor expression has not been thoroughly correlated with placental morphologic development across gestation in cats. We postulate that changes in placental vessel morphology can be appreciated as consequences of dynamic expression of angiogenic signaling agents. Here, we characterized changes in placental morphology alongside expression analysis of angiogenic factor splice variants and receptors throughout pregnancy in domestic shorthair cats. We observed increased vascular and lamellar density in the lamellar zone during mid-pregnancy. Immunohistochemical analysis localized the vascular endothelial growth factor A (VEGF-A) receptor KDR to endothelial cells of the maternal and fetal microvasculatures. PlGF and its principal receptor Flt-1 were localized to the trophoblasts and fetal vasculature. VEGF-A was found in trophoblast cells and associated with endothelial cells. We detected expression of two Plgf splice variants and four Vegf-a variants. Quantitative real-time polymerase chain reaction analysis showed upregulation of mRNAs encoding pan Vegf-a and all Vegf-a splice forms at gestational days 30-35. Vegf-A showed a marked relative increase in expression during mid-pregnancy, consistent with the pro-angiogenic changes seen in the lamellar zone at days 30-35. Flt-1 was upregulated during late pregnancy. Plgf variants showed stable expression during the first two-thirds of pregnancy, followed by a marked increase toward term. These findings revealed specific spatiotemporal expression patterns of VEGF-A family members consistent with pivotal roles during normal placental development.

Maternal exposure to nano-titanium dioxide impedes fetal development via endothelial-to-mesenchymal transition in the placental labyrinth in mice

BackgroundExtensive production and usage of commercially available products containing TiO2 NPs have led to accumulation in the human body. The deposition of TiO2 NPs has even been detected in the human placenta, which raises concerns regarding fetal health. Previous studies regarding developmental toxicity have frequently focused on TiO2 NPs < 50 nm, whereas the potential adverse effects of large-sized TiO2 NPs received less attention. Placental vasculature is essential for maternal–fetal circulatory exchange and ensuring fetal growth. This study explores the impacts of TiO2 NPs (100 nm in size) on the placenta and fetal development and elucidates the underlying mechanism from the perspective of placental vasculature. Pregnant C57BL/6 mice were exposed to TiO2 NPs by gavage at daily dosages of 10, 50, and 250 mg/kg from gestational day 0.5–16.5.ResultsTiO2 NPs penetrated the placenta and accumulated in the fetal mice. The fetuses in the TiO2 NP-exposed groups exhibited a dose-dependent decrease in body weight and length, as well as in placental weight and diameter. In vivo imaging showed an impaired placental barrier, and pathological examinations revealed a disrupted vascular network of the labyrinth upon TiO2 NP exposure. We also found an increase in gene expression related to the transforming growth factor-β (TGF-β) -SNAIL pathway and the upregulation of mesenchymal markers, accompanied by a reduction in endothelial markers. In addition, TiO2 NPs enhanced the gene expression responsible for the endothelial-to-mesenchymal transition (EndMT) in cultured human umbilical vein endothelial cells, whereas SNAIL knockdown attenuated the induction of EndMT phenotypes.ConclusionOur study revealed that maternal exposure to 100 nm TiO2 NPs disrupts placental vascular development and fetal mice growth through aberrant activation of EndMT in the placental labyrinth. These data provide novel insight into the mechanisms of developmental toxicity posed by NPs.

The placental vasculature is affected by changes in gene expression and glycogen-rich cells in a diet-induced obesity mouse model.

Maternal obesity is a risk factor for pregnancy complications. Obesity caused by a high-fat diet (HFD) may alter maternal glucose/glycogen metabolism. Here, our objective was to investigate whether the placental vasculature is altered via changes in gene expression and glycogen-rich cells using a preclinical mouse model of diet-induced obesity. We subjected female FVB/N mice to one of three feeding regimens: regular chow (RC) given at preconception and during pregnancy (Control); RC given at preconception and then a HFD during pregnancy (HFD-P); or HFD initiated 4 weeks preconception and during pregnancy (HFD-PreCP). Daily food consumption and weekly maternal weights were recorded. Maternal blood glucose levels were measured at preconception and 4 gestational epochs (E6.5-E9.5, E10.5-E12.5, E13.5-E15.5, E16.5-E19.5). At E8.5-E16.5, total RNA in placentas were isolated for gene expression analyses. Placentas were also collected for HE and periodic acid Schiff's (PAS) staining and glycogen content assays. Dams in the HFD-P and HFD-PreCP groups gained significantly more weight than controls. Pre- and antenatal glucose levels were also significantly higher (15%-30%) in HFD-PreCP dams. Expression of several placental genes were also altered in HFD dams compared with controls. Consumption of the HFD also led to phenotypic and morphologic changes in glycogen trophoblasts (GlyTs) and uterine natural killer (uNK) cells. Alterations in vascularity were also observed in the labyrinth of HFD-PreCP placentas, which correlated with decreased placental efficiency. Overall, we observed that a HFD induces gestational obesity in mice, alters expression of placental genes, affects glucose homeostasis, and alters glycogen-positive GlyTs and uNK cells. All these changes may lead to impaired placental vascular development, and thus heighten the risk for pregnancy complications.

Maternal CXCR4 deletion results in placental defects and pregnancy loss mediated by immune dysregulation.

CXCR4 is a key regulator of the development of NK cells and DCs, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. Our study demonstrates that adult-induced global genetic CXCR4 deletion, but not uterine-specific CXCR4 deletion, was associated with increased pregnancy resorptions and decreased litter size. CXCR4-deficient mice had decreased NK cells and increased granulocytes in the decidua, along with increased leukocyte numbers in peripheral blood. We found that CXCR4-deficient mice had abnormal decidual NK cell aggregates and NK cell infiltration into trophoblast areas beyond the giant cell layer. This was associated with low NK cell expression of granzyme B, a NK cell granule effector, indicative of NK cell dysfunction. Pregnancy failure in these mice was associated with abnormalities in placental vascular development and increased placental expression of inflammatory genes. Importantly, adoptive BM transfer of WT CXCR4+ BM cells into CXCR4-deficient mice rescued the reproductive deficits by normalizing NK cell function and mediating normal placental vascular development. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development, and pregnancy maintenance.

The Procoagulant Phospholipid Dependent Clotting Time and the Initiation Phase of Thrombin Generation Test Are Mandatory for the Evaluation of the Risk for Severe Early Onset Preeclampsia

Bakground: Preeclampsia occurs in up to 7% of pregnancies in Western Countries and is a leading cause of maternal and fetal morbidity and mortality. Classification of preeclampsia is based on the timing of symptoms' onset and the severity of the clinical status. Accordingly, early and late preeclampsia are characterized by symptom onset before or after 32-34 weeks of gestation respectively. Pathogenesis of preeclampsia is characterized by abnormal placental vascular development with impaired invasion of the uterine spiral arteries by trophoblasts, resulting in fetal complications and maternal endothelial dysfunction. Intact antithrombotic properties of the endothelial cells and efficient regulation of thrombin generation and platelet activation at the microenvironment of the uterus are necessary conditions for successful trophoblast invasion and development of feto-maternal circulation during normal pregnancy. , Prompt identification of pregnant women at risk of preeclampsia worsening could help to anticipated therapeutic intervention and improvement of the clinical outcome. Aim: The ROADMAP-Early Onset Preeclampsia study (ROADMAP-EOP) aiming to respond to this unmet need assessed the clinical relevance of biomarkers of hypercoagulability and endothelial activation for prompt identification of pregnant women at high risk of preeclampsia. Materials and Methods: An observational single center retrospective case-control study was conducted in pregnant women diagnosed with preeclampsia from July 2020 to July 2021. Pregnant women were retrospectively enrolled upon EOP diagnosis and stratified in mild EOP group (n=34) and severe EOP group (n=15 according to the criteria of the International Society for the Study of Hypertension in Pregnancy ). Eligible women were included in the study before initiation of any treatment for preeclampsia. The control group (n=35) consisted of women with uncomplicated pregnancy. All women were assessed with thromboelastometry, Calibrated Automated Thrombo-gram®, tissue factor activity (TFa), Procoagulant phospholipid dependent clotting time (Procoag-PPL), Proteins S, TFPI, D-dimer, antithrombin, thrombomodulin, fibrinogen prothrombin time and activated partial thromboplastin time. Primary and secondary end points were severe EOP and EOP respectively. Principal component analysis (PCA) was performed to check for associations among the biomarkers and the clinical out-come. Results: There were no significant differences regarding age, gravidity, gestational age and the body mass index (BMI) between EOP groups and normal pregnancy as well as within the EOP groups. Platelet counts were similar in healthy pregnant women, and mild EOP group, and significantly lower in severe EOP (p&amp;lt;0.05). No other statistically significant differences were found between-groups. The PCA showed that the repartition of data allowed to discriminate the patients with EOP from healthy pregnant women as well as patients with mild EPO from those with severe EOP. When biomarkers of hypercoagulability were considered according to the severity of EOP in PCA analysis the lag-time and PPL clotting time were independently associated with the risk of severe EOP (Table 1and Figure 1)). The increase of the lag-time by 1 min was associated with a 20.2-fold increase of the risk of severe EOP. The marginal effects curve shows that for a lag-time longer than 2.6 min, the probability of severe EOP was higher than 50% .Longer Procoag-PPL clotting time was associated with lower risk of severe EOP. The marginal effects curve, showed that for Procoag-PPL clotting time longer than 58.75 sec the probability of severe EOP decreased by 50%. These data suggest that a biological score composed of the Procoag-PPL® clotting time and thrombin generation (Throbmogram-Thrombinoscope® PPP-reagent 1 pM-TF as-say) could be a useful tool to identify pregnant women with high probability of EOP Conclusion: the Procoag-PPL® clotting time and thrombin generation assay reflect cellular derived hypercoagulability and allow accurate screening of pregnant women for the prompt identification of those at risk of EOP and the evaluation of its severity. This concept has to be validated in a large prospective cohort trial. . An external validation of the proposed methodology needs to be performed in a large prospective observational study.

Elevated gestational testosterone impacts vascular and uteroplacental function

Maternal vascular adaptations to establish an adequate blood supply to the uterus and placenta are essential for optimal nutrient and oxygen delivery to the developing fetus in eutherian mammals, including humans. Numerous factors contribute to maintaining appropriate hemodynamics and placental vascular development throughout pregnancy. Failure to achieve or sustain these pregnancy-associated changes in women is strongly associated with an increased risk of antenatal complications, such as preeclampsia, a hypertensive disorder of pregnancy. The precise etiology of preeclampsia is unknown, but emerging evidence points to a potential role for androgens. The association between androgens and maternal cardiovascular and placental function merits particular attention due to the notable 2- to 3-fold elevated plasma testosterone (T) levels observed in preeclampsia. T levels in preeclamptic women positively correlate with vascular dysfunction, and preeclampsia is associated with increased androgen receptor (AR) levels in placental tissues. Moreover, animal studies replicating the pattern and magnitude of T increase observed in preeclamptic pregnancies have reproduced key features of preeclampsia, including gestational hypertension, endothelial dysfunction, heightened vasoconstriction to angiotensin II, impaired spiral artery remodeling, placental hypoxia, reduced nutrient transport, and fetal growth restriction. Collectively, these findings suggest that AR-mediated activity plays a significant role in the clinical presentation of preeclampsia. This review critically evaluates this hypothesis, considering both clinical and preclinical evidence.

KLF4 down-regulation underlies placental angiogenesis impairment induced by maternal glucose intolerance in late pregnancy

Maternal glucose intolerance in late pregnancy can easily impair pregnancy outcomes and placental development. The impairment of placental angiogenesis is closely related to the occurrence of glucose intolerance during pregnancy, but the mechanism remains largely unknown. In this study, the pregnant mouse model of maternal high-fat diet and endothelial injury model of porcine vascular endothelial cells (PVECs) was used to investigate the effect of glucose intolerance on pregnancy outcomes and placental development. Feeding pregnant mice, a high-fat diet was shown to induce glucose intolerance in late pregnancy, and significantly increase the incidence of resorbed fetuses. Moreover, a decrease was observed in the proportion of blood sinusoids area and the expression level of CD31 in placenta, indicating that placental vascular development was impaired by high-fat diet. Considering that hyperglycemia is an important symptom of glucose intolerance, we exposed PVECs to high glucose (50 mM), which verified the negative effects of high glucose on endothelial function. Bioinformatics analysis further emphasized that high glucose exposure could significantly affect the angiogenesis-related functions of PVECs and predicted that Krüppel-like factor 4 (KLF4) may be a key mediator of these functional changes. The subsequent regulation of KLF4 expression confirmed that the inhibition of KLF4 expression was an important reason why high glucose impaired the endothelial function and angiogenesis of PVECs. These results indicate that high-fat diet can aggravate maternal glucose intolerance and damage pregnancy outcome and placental angiogenesis, and that regulating the expression of KLF4 may be a potential therapeutic strategy for maintaining normal placental angiogenesis.

Maternal chronic caffeine intake impairs fertility, placental vascularization and fetal development in mice

Caffeine is commonly consumed by pregnant women to avoid fatigue or as a habit. However, it is not clearly determined its side effects to the conceptuses. This study evaluated placental morphofunctional alterations after maternal chronic caffeine intake and the effects on fetal growth. Female Swiss mice received, via gavage, caffeine doses (either 60, 120 or 240 mg/kg/day) seven days before mating until gestational days-(GD) 11.5 or 17.5. Fetal biometrical parameters were assessed, and placentae were either submitted to histomorphometrical or molecular evaluation of angiogenesis (placental growth factor-1[PlGF-1]), apoptosis (Caspase-3) and proliferation (Ki-67) markers (evaluated in Swiss dams) and to intravital microscopy (evaluated in C57BL/6 dams). Caffeine exposed fetuses exhibited intrauterine growth restriction in a sex-dependent manner, with greater commitment of female fetuses (P < 0.05). In addition, placentae from dams that received 120 mg/kg/day showed less irrigation by maternal blood and greater development of fetal vasculature, characterized by higher number of larger vessels (P < 0.05). Although no effects on apoptosis (Caspase-3) and angiogenesis (PlGF-1) were observed, dams treated with 60 mg/kg/day showed greater placental cell proliferation (Ki-67 staining) at GD 11.5 (P < 0.05). The group treated with 240 mg/kg/day exhibited only one pregnant dam for each gestational age, suggesting that this high caffeine consumption may compromise fertility. Taken together, even in the doses currently ingested by many pregnant women, caffeine has detrimental effects on placental vasculature and fetal development in mice. Therefore, our results strongly suggest that caffeine consumption in human pregnancies greater than the recommended doses should be avoided.

First trimester hofbauer Cells from Pregnancies with a higher risk of developing preeclampsia display differences in cell surface marker expression, cytokine secretion and regulation of placental vascular development compared to pregnancies with a normal risk

First trimester hofbauer Cells from Pregnancies with a higher risk of developing preeclampsia display differences in cell surface marker expression, cytokine secretion and regulation of placental vascular development compared to pregnancies with a normal risk

Sequential disruptions to inflammatory and angiogenic pathways and risk of spontaneous preterm birth in Malawian women

Preterm birth is a leading cause of death in children under five years of age. We hypothesized that sequential disruptions to inflammatory and angiogenic pathways during pregnancy increase the risk of placental insufficiency and spontaneous preterm labor and delivery. We conducted a secondary analysis of inflammatory and angiogenic analytes measured in plasma samples collected across pregnancy from 1462 Malawian women. Women with concentrations of the inflammatory markers sTNFR2, CHI3L1, and IL18BP in the highest quartile before 24weeks gestation and women with anti-angiogenic factors sEndoglin and sFlt-1/PlGF ratio in the highest quartile at 28-33weeks gestation had an increased relative risk of preterm birth. Mediation analysis further supported a potential causal link between early inflammation, subsequent angiogenic dysregulation detrimental to placental vascular development, and earlier gestational age at delivery. Interventions designed to reduce the burden of preterm birth may need to be implemented before 24weeks of gestation.

Estrogen Actions in Placental Vascular Morphogenesis and Spiral Artery Remodeling: A Comparative View between Humans and Mice.

Estrogens, mainly 17β-estradiol (E2), play a critical role in reproductive organogenesis, ovulation, and fertility via estrogen receptors. E2 is also a well-known regulator of utero-placental vascular development and blood-flow dynamics throughout gestation. Mouse and human placentas possess strikingly different morphological configurations that confer important reproductive advantages. However, the functional interplay between fetal and maternal vasculature remains similar in both species. In this review, we briefly describe the structural and functional characteristics, as well as the development, of mouse and human placentas. In addition, we summarize the current knowledge regarding estrogen actions during utero-placental vascular morphogenesis, which includes uterine angiogenesis, the control of trophoblast behavior, spiral artery remodeling, and hemodynamic adaptation throughout pregnancy, in both mice and humans. Finally, the estrogens that are present in abnormal placentation are also mentioned. Overall, this review highlights the importance of the actions of estrogens in the physiology and pathophysiology of placental vascular development.

Elevated Placental microRNA-155 Is a Biomarker of a Preeclamptic Subtype

Preeclampsia is a complicated syndrome with marked heterogeneity. The biomarker-based classification for this syndrome is more constructive to the targeted prevention and treatment of preeclampsia. It has been reported that preeclamptic patients had elevated microRNA-155 (miR-155) in placentas or circulation. Here, we investigated the characteristics of patients with high placental miR-155 (pl-miR-155). Based on the 95th percentile (P95) of pl-miR-155 in controls, preeclamptic patients were divided into high miR-155 group (≥P95) and normal miR-155 group (<P95). The changes of placental pathology, clinical manifestations, and placental transcriptome of preeclamptic patients were clustered by t-distributed stochastic neighbor embedding and hierarchical clustering analysis. The placental restricted miR-155 overexpression mouse model was constructed, and the phenotype, placental pathology, and transcriptome were evaluated. Furthermore, the therapeutic potential of antagonist of miR-155 was explored by administrating with antagomir-155. About one-third of preeclamptic patients had high pl-miR-155 expression, which was positively correlated with circulating miR-155 levels. These patients could be clustered as 1 group, according to clinical manifestation, placental pathology, or transcriptomes by t-distributed stochastic neighbor embedding and hierarchical clustering analysis. Further, the pregnant mice with placental restricted miR-155 overexpression could simulate the changes of clinical signs, pathology, and transcriptome of placentas in patients with high pl-miR-155. AntagomiR-155 treatment relieved the preeclampsia-like phenotype and improved the placental vascular development in mice. There is at least 1 type of preeclampsia with upregulated miR-155 presenting more severe clinical manifestations. MiR-155 may be a potential therapeutic target in patients with high pl-miR-155.

Extracellular Vesicles From Women With Severe Preeclampsia Impair Vascular Endothelial Function

(Anesth Analg. 2022;134:713–723) Preeclampsia causes worldwide maternal and neonatal morbidity and mortality. Previous studies confirm the placenta is heavily related to preeclampsia and vascular dysfunction likely caused by pro-angiogenic and anti-angiogenic factors due to changes in uteroplacental blood flow and oxygenation from abnormal trophoblastic invasion of the uterine spiral arterioles. A previous study involving a mouse model supports the idea of extracellular vesicles (EVs), particles which interact with microRNA and impact endocrine or paracrine organs, from the placenta being a main culprit for triggering preeclampsia. All pregnancies show levels of placenta-derived EVs (pEVs), but those with preeclampsia show an increased level, impacting the growth and weight gain of the child, levels of endothelial nitric oxide synthase (eNOS) to endothelial cells leading to irregular embryo development, implantation, trophoblast invasion, placental vascular development, function, and increased level of endothelial dysfunction. This study primarily measures the effect of EVs from both severe preeclampsia and normotensive patients on human aortic endothelial cells to test the hypothesis that preeclamptic EV cargo impairs endothelial function and regulation of NO signaling.

Aquaporin-8 overexpression is involved in vascular structure and function changes in placentas of gestational diabetes mellitus patients.

To study the role and mechanism of aquaporin-8 (AQP8) in placental vascular development in gestational diabetes mellitus (GDM), hematoxylin-eosin staining and immunohistochemistry were utilized to analyze the histopathological changes in placentas in GDM patients. Transwell, CCK-8, and tube formation assays were performed to examine cell migration, proliferation, and tube formation. AQP8, vascular cell adhesion molecule 1 (VCAM-1), tumor necrosis factor alpha (TNF)-α, and vascular endothelial growth factor (VEGF)-A expression levels were investigated. Relative to the control group, the placentas in the GDM group showed morphological changes, the number of microvessels in the placental villi arterioles was significantly higher, and the area of microvessels in the arterioles of placental villi was significantly lower. The expression levels of VCAM-1, TNF-α, VEGF-A, and AQP8 in the GDM placentas and human umbilical vein endothelial cells (HUVECs) stimulated by high glucose were significantly higher than those in the control group, and AQP8 was located in placental endothelial cells. Overexpression of glucose and AQP8 inhibited tube formation, migration, and proliferation in HUVECs. High glucose levels can induce dysfunction in vascular endothelial cells and lead to pathological changes in the placental vascular structure in GDM. AQP8 overexpression in placental GDM can inhibit endothelial cell behavior, cause endothelial cell dysfunction, and further participate in the occurrence and development of GDM placental vascular lesions.