Vascularization Of Placenta Research Articles

ТHE METABOLIC ASPECTS OF PREECLAMPSIA DEVELOPMENT

Complications associated with preeclampsia (PE) include fetal growth retardation, premature birth, prenatal and postpartum hemorrhage, perinatal loss, and more. Obese women have an increased risk of developing PE, probably due to impaired placental development due to altered metabolic homeostasis. The aim was to generalize current knowledge about the role of risk factors associated with obesity and hypercholesterolemia in PE with an emphasis on the results of preclinical models. Material and methods. In reviewing the literature, we used Medline systems from PubMed (2011). The search was adapted for Embase (2014-2022) and Scopus (2015-2022). The inclusion criteria were: the effect of obesity on pregnancy; experimental models of the pathogenesis of obesity during pregnancy; the features of predictive diagnosis of obese women at the stage of preconception and during pregnancy; features of antenatal care in obese women. The study was performed at Vinnytsya National Pirogov Memorial Medical University, according to research work № 0121U109141 “Optimization of early diagnosis and preventive treatment of perinatal complications caused by gestational endotheliopathy.” Results. Inflammatory cytokines from maternal adipose tissue and hypercholesterolemia have been associated with systemic inflammation, hypertension, and other adverse effects associated with PE. The main pathways of the negative influence of obesity on the genesis of PE were realized due to the manifested gestational endotheliopathy. Decreases in adipose tissue and associated adipokines were associated with optimization of placental angiogenesis and an overall improvement in the adverse effects associated with PE. Conclusions. Increased maternal adipose tissue mass and cholesterol levels contribute to metabolic disorders and systemic inflammation, which may contribute to the development of gestational endotheliopathy and subsequent abnormal placenta vascularization. Further research will need to further clarify the contribution of pharmacotherapy, as well as some lifestyle adjustments, including preconceptional weight loss and the results of PE in women at high risk of obesity.

Exerkine apelin reverses obesity-associated placental dysfunction by accelerating mitochondrial biogenesis in mice.

Maternal exercise (ME) protects against adverse effects of maternal obesity (MO) on fetal development. As a cytokine stimulated by exercise, apelin (APN) is elevated due to ME, but its roles in mediating the effects of ME on placental development remain to be defined. Two studies were conducted. In the first study, 18 female mice were assigned to control (CON), obesogenic diet (OB), or OB with exercise (OB/Ex) groups (n = 6); in the second study, the same number of female mice were assigned to three groups; CON with PBS injection (CD/PBS), OB/PBS, or OB with apelin injection (OB/APN). In the exercise study, daily treadmill exercise during pregnancy significantly elevated the expression of PR domain 16 (PRDM16; P < 0.001), which correlated with enhanced oxidative metabolism and mitochondrial biogenesis in the placenta (P < 0.05). More importantly, these changes were partially mirrored in the apelin study. Apelin administration upregulated PRDM16 protein level (P < 0.001), mitochondrial biogenesis (P < 0.05), placental nutrient transporter expression (P < 0.001), and placental vascularization (P < 0.01), which were impaired due to MO (P < 0.05). In summary, MO impairs oxidative phosphorylation in the placenta, which is improved by ME; apelin administration partially mimics the beneficial effects of exercise on improving placental function, which prevents placental dysfunction due to MO.NEW & NOTEWORTHY Maternal exercise prevents metabolic disorders of mothers and offspring induced by high-fat diet. Exercise intervention enhances PRDM16 activation, oxidative metabolism, and vascularization of placenta, which are inhibited due to maternal obesity. Similar to maternal exercise, apelin administration improves placental function of obese dams.

Neurodevelopmental outcome of children born to mothers with congenital heart disease

Congenital heart disease (CHD) can lead to under vascularization of placenta, which can affect fetal development and subsequent neurological outcome. No data are currently available regarding neurodevelopmental outcome of children born to mothers with CHD. Characteristics of pregnancy, birth and neonatal period, items of neurodevelopment during infancy recorded in health book, need for speech therapist, physiotherapist, school helper and grade repetition were retrospectively collected in children under 10 years old born to CHD mothers followed up in 5 French congenital heart disease centres, and compared to a control population (children and brotherhood from mother consulting in 2 paediatric traumatology emergency rooms). Children under 7 years old of both groups were prospectively screened for neurodevelopmental trouble using the neurodevelopmental test developed by the “Haute Autorité de Santé” (HAS). One hundred and nineteen children from 83 CHD mothers and 122 children from 118 control mothers were included. Children from CHD mothers were born earlier (37.9 ± 2.6 vs. 39.3 ± 1.5 WA) and with a higher rate of prematurity (17.6 vs. 4.9%). They displayed lower birth weights (2910 ± 650 vs. 3370 ± 500 g), lower APGAR scores at 1 minute (8.6 ± 2.3 vs. 9.3 ± 1.5) and a smaller head circumference at 9 months (44.7 ± 1.4 vs. 45.3 ± 1.4 cm). There was no difference in the age of walking and head circumference at 24 months, as well as grade repetitions and need for speech therapist, physiotherapist, or school helper. The HAS neurodevelopmental test suspected trouble in 5.9% of children from CHD mothers and 11.5% of control children (NS). Despite increased prematurity and worse APGAR score, children from mothers with CHD appear not to show symptoms of neurodevelopment impairment in our study.

Immune and Apoptosis Mechanisms Regulating Placental Development and Vascularization in Preeclampsia

Preeclampsia is the most severe type of hypertensive disorder of pregnancy, affecting one in 10 pregnancies worldwide and increasing significantly maternal and neonatal morbidity and mortality. Women developing preeclampsia display an array of symptoms encompassing uncontrolled hypertension and proteinuria, with neurological symptoms including seizures at the end of pregnancy. The main causes of preeclampsia are still unknown. However, abnormal placentation and placenta vascularization seem to be common features in preeclampsia, also leading to fetal growth restriction mainly due to reduced placental blood flow and chronic hypoxia. An over activation of maternal immunity cells against the trophoblasts, the main cells forming the placenta, has been recently shown as an important mechanism triggering trophoblast apoptosis and death. This response will further disrupt the remodeling of maternal uterine arteries, in a first stage, and the formation of new placental vessels in a later stage. A consequent chronic hypoxia stress will further contribute to increase placental stress and exacerbate systemic circulatory changes in the mother. The molecular mechanisms driving these processes of apoptosis and anti-angiogenesis are also not well-understood. In this review, we group main evidences suggesting potential targets and molecules that should be better investigated in preeclampsia. This knowledge will contribute to improve therapies targeting a better placenta formation, having a positive impact on maternal disease prevention and on fetal development.

Genetic and nongenetic profiling of milk pregnancy-associated glycoproteins in Holstein cattle

Pregnancy-associated glycoproteins (PAG) are secreted by the trophoblast and are detectable in maternal circulation around the time of attachment of the fetal placenta, as well as in blood and milk throughout gestation. The understanding of the genetic mechanisms controlling PAG levels can confer advantages for livestock breeding programs given the precocity and the ease of obtaining this phenotype from routine pregnancy diagnosis. The aim of this study was to characterize PAG levels by estimating genetic parameters and correlations with other dairy traits, and to identify genomic regions and candidate genes associated with PAG levels in milk. The PAG data consisted of pregnancy diagnoses using commercial assays from 2012 to 2017, and genotype data consisted of 54,123 SNP markers for 2,352 individuals (embryos and dams). The model included contemporary group (herd, year, and season) and embryo age as fixed effects, and random embryonic (direct) and maternal (indirect) genetic effects. Using genomic data, the estimated heritability for direct and maternal genetic effects (± standard deviations) were 0.23 ± 0.05 and 0.11 ± 0.05, respectively. The genetic correlation between these effects was almost zero (0.001 ± 0.06). A preliminary analysis revealed low correlations between milk PAG levels and other dairy traits. The genome-wide association analysis was performed using 2 approaches: single-marker and single-step using all markers. Four genomic regions with direct genetic effects were detected on Bos taurus autosome (BTA) 6, BTA7, BTA19, and BTA29 of the embryonic genome. The BTA29 locus was within the bovine PAG gene cluster, suggesting a cis-regulatory quantitative trait locus on the PAG expression. However, other associations, without an obvious link to PAG expression, could be related to the transportation of PAG and their concentration in milk. Only 1 region from the maternal genome, on BTA4, had a significant indirect effect, where WNT2 is a candidate gene related to placenta vascularization and gestation health. Collectively, our results suggest a moderate genetic control of milk PAG levels from both maternal and fetal genomes, but larger studies are needed to fully evaluate the usefulness of milk PAG in the genetic evaluation of fetal growth and cow fertility.

Retrospective, case-controlled stereology assessment of vascularization in placentas of HIV-exposed, uninfected (HEU) children

Retrospective, case-controlled stereology assessment of vascularization in placentas of HIV-exposed, uninfected (HEU) children

Ex vivo magnetic resonance angiography to explore placental vascular anatomy

IntroductionA normal placenta development is crucial for a successful pregnancy. In case of major obstetric complications such as intra-uterine growth restriction, the placental vascularization morphological alteration at macroscopic level is less known than that at microscopic scale. Ex vivo MRA has the potential to visualize whole fresh human placental vasculature fast and efficiently but can be hampered by contrast agent extravasation problem. This study aimed to provide an optimized ex vivo MRA protocol to acquire understanding of global human placenta vasculature morphology. MethodsSix fresh normal human placentas were imaged with two contrast agents (i.e. Gd-chelate and pump oil) using different imaging parameters on a 3T clinical MR scanner (GE). The contrast to noise ratio, signal to noise ratio and enhancement efficiency were assessed in order to decide which contrast agent and imaging protocol was better. In the end, morphology indices were measured based on the 3D vasculature models reconstructed from the placentas imaged with the optimized protocol. ResultsWith the same imaging parameters, the CNR and the enhancement efficiency of images enhanced with pump oil were superior to those using Gd-chelate. Enhanced by pump oil, an optimized ex vivo MRA protocol was determined, leading to a clear 3D visualization and reconstruction of human placenta vascularization. DiscussionThe proposed ex vivo MRA method is easy to manipulate, and can be used to investigate the human placental vasculature morphology. The acquired data are of good quality and can be used for characterization of placenta vascularization morphology.

Contribution of growth factors and cytokines in the pathophysiology of human placenta in gestational diabetes mellitus

G diabetes mellitus (GDM) is one of the most common complications of the pregnancy and affects 15% of pregnant women worldwide. Prevalence of GDM has increased from 10-100% in several race/ethnic groups over the last 20 years, reflecting the underlying increase in type 2 diabetes. Five of the top 10 countries for diabetes prevalence in 2010 were in the Gulf region. There were 303,700 known cases of diabetes in Qatar in 2014 and the number is growing each year. Children of women with GDM have an increased risk of development of cardiovascular and metabolic diseases which include obesity, type 2 diabetes and metabolic syndrome. GDM also increases the risk of development of neurologic dysfunction in offspring born to women with GDM in their childhood or adulthood. Children of women with GDM are more likely to be obese and diabetic in childhood and adulthood. GDM also increases the risk of adverse pregnancy outcomes, including preeclampsia, birth injuries, macrosomia and neonatal hypoglycemia, respiratory distress syndrome, neonatal cardiac dysfunction and stillbirth. The human placenta is located at the interface between mother and fetal blood circulation and has a central role both as a producer as well as a target of several molecules that are involved in placental development and function. We have investigated the role of cytokines and growth factors in the pathophysiology of placenta in the GDM. We have performed a Pubmed search with key words placenta, GDM, placental villi, vascularization, cytokines, growth factors, inflammation, hypoxia, oxidative stress and pathophysiology. We have investigated differences in the development and vascularization of placenta, their underlying causes and impact on feto-maternal health through literature review. We have also identified gaps in the literature and researched questions that need to be answered to completely understand the central role of placenta in the GDM. This study is important in understanding the pathophysiology of placenta due to changes in the location and expression of cytokines and growth factors in the placental cells of women suffering from GDM. It is necessary to understand these mechanisms in order to develop treatments to reverse the effects of cytokines and growth factors on placental malfunctioning, which in turn, will result in improved mother and child health.

Assessment of therapeutic efficacy of miR-126 with contrast-enhanced ultrasound in preeclampsia rats

Preeclampsia is a pregnancy-specific syndrome characterized by high blood pressure and proteinuria, which has a pathophysiology of insufficient placental blood perfusion. MicroRNA-126 (miR-126), an angiogenesis-related miRNA, has been proved to play a significant role in endothelial cells response to ischemia in vitro and in vivo. However, whether miR-126 has therapeutic potential in vasculogenesis of preeclampsia placenta remains uncertain. In this study, we focused our attention on this unsolved problem. First, we established the preeclampsia animal model and over-expressed miR-126 in vivo using a specific agomir. Then we described the effects of miR-126 on placental vasculogenesis in preeclampsia rats, including the evaluation of placental blood perfusion using microbubbles-assisted contrast-enhanced ultrasonography (CEUS), placental histology, immunohistochemistry and pregnancy outcome. Finally, we investigated the possible target gene and pathway that miR-126 modulates. Together, our results showed that preeclampsia animal with over-expressed miR-126 had higher pup weight, placenta weight and proportion of live pups. Quantification of uteroplacental perfusion by CEUS and CD34 staining of placental tissue revealed that blood volume and microvessel density increased in miR-126 treated group. MiR-126 was related to PIK3R2 down-regulation and Akt activation within placenta, which had impacts on vascularization of placenta. Therefore, miR-126 may be an efficient gene therapy to promote angiogenesis and blood perfusion in preeclampsia placenta.

Analysis of placenta vascularization in patients with uterine altered artery Doppler flow velocity exams

One of the frequent questions in obstetric practice is to determine placental vascular changes that may account for abnormal Doppler flow velocity alterations in maternal uterine vessels from women and fetuses without pregnancy pathology. A retrospective morphometric study was realized using 27 placentas from patients submitted for Doppler flow velocity exam during pregnancy. The placentas were morphologically examined using hematoxylin-eosin staining. Measurements of villi were made with the use of a video camera coupled to a common light microscope and a computer with automatic image analyzing software. Of the 27 placentas, 13 (48%) were of patients showing unaltered Doppler and 14 (52%) showing altered Doppler. The number of stem villi vessels was significantly larger in the placentas of patients with Doppler exam alterations (P = 0.003). This group also presented greater stem villi vessel thickness, although without significant difference. The number of intermediary and terminal villi vessels was greater in the placentas of patients with altered Doppler exams (P < 0.001), and a greater terminal villi area was observed in these cases (P < 0.001). The morphological proof that uterine artery Doppler flow velocity exam alterations are associated with placental vascular alterations demonstrates the importance of this exam during prenatal care, even in the absence of maternal-fetal alterations.

650: Placenta vascularization potential is already partly determined by 11-14 weeks

650: Placenta vascularization potential is already partly determined by 11-14 weeks

Maternal Tgif is required for vascularization of the embryonic placenta

The mammalian placenta is the site of exchange of nutrients and waste between mother and embryo. In humans, placental insufficiency can result in intrauterine growth retardation, perinatal death and spontaneous abortion. We show that in C57BL/6J mice a null mutation in the gene encoding the transcriptional corepressor, Tgif, causes placental defects. The major defects are decreased vascularization of the placenta, due to a decrease in the fetal blood vessels, and decreased expression of the gap junction protein Gjb2 (Cx26). These defects result in severe growth retardation in a proportion of Tgif null embryos in Tgif heterozygous mothers, and an overall growth delay in Tgif null animals. Placental defects are much more severe if the mother also completely lacks Tgif function, and placentas from heterozygous Tgif embryos are defective in a Tgif null mother. Embryo transfer experiments show that even the placenta from a wild type embryo is compromised in the absence of maternal Tgif. These results demonstrate that Tgif functions in the normal development of the placenta, and suggest a role for maternal factors in regulating the morphogenesis of embryonically-derived placental tissues.

Increased activity of hypoxia-inducible factor 1 is associated with early embryonic lethality in Commd1 null mice.

COMMD1 (previously known as MURR1) belongs to a novel family of proteins termed the copper metabolism gene MURR1 domain (COMMD) family. The 10 COMMD family members are well conserved between vertebrates, but the functions of most of the COMMD proteins are unknown. We recently established that COMMD1 is associated with the hepatic copper overload disorder copper toxicosis in Bedlington terriers. Recent in vitro studies indicate that COMMD1 has multiple functions, including sodium transport and NF-kappaB signaling. To elucidate the function of Commd1 in vivo, we generated homozygous Commd1 null (Commd1(-/-)) mice. Commd1(-/-) embryos died in utero between 9.5 and 10.5 days postcoitum (dpc), their development was generally retarded, and placenta vascularization was absent. Microarray analysis identified transcriptional upregulation of hypoxia-inducible factor 1 (HIF-1) target genes in 9.5-dpc Commd1(-/-) embryos compared to normal embryos, a feature that was associated with increased Hif-1alpha stability. Consistent with these observations, COMMD1 physically associates with HIF-1alpha and inhibits HIF-1alpha stability and HIF-1 transactivation in vitro. Thus, this study identifies COMMD1 as a novel regulator of HIF-1 activity and shows that Commd1 deficiency in mice leads to embryonic lethality associated with dysregulated placenta vascularization.

Angiogenesis during primate placentation in health and disease.

Normal embryonic development is dependent upon a sufficient oxygen, nutrient and waste exchange through the placenta. In primates including humans, this exchange is attained by successful haemochorial placentation which requires the transformation of maternal intramyometrial spiral arterioles by trophoblast invasion to gain uteroplacental circulation, and establishment and maintenance of a competent fetoplacental vasculature. Thus, trophoblast and endothelial cell differentiation, proliferation and invasion occurring during placentation have to be tightly regulated. This review focuses on the diverse developmental steps during haemochorial placentation in humans and other primates and the possible involvement of angiogenic growth factors (vascular endothelial growth factor (VEGF) and angiopoietins (Ang)) in these processes, highlighting the importance of specific actions of angiogenic ligand-receptor pairs. It is hypothesized that VEGF/VEGF-R1 and Ang-1/Tie receptor 2 (Tie-2) may regulate trophoblast differentiation and invasion; VEGF/VEGF-R2 and Ang-1/Tie-2 may promote fetoplacental vascular development and stabilization; and Ang-2/Tie-2 may be involved in maternal vascular remodelling. The importance of a tight regulation of angiogenic factors and their endogenous antagonists for normal development of the placenta is demonstrated by failure of this system, resulting in abnormal placenta vascularization and trophoblast invasion associated with intrauterine growth retardation or pre-eclampsia.