Altered placental expression of genes related to Vitamin D Metabolism and their correlation with spiral artery remodeling in Preeclamptic Women

Background: Several studies reveals the correlation of preeclampsia (PE) with low vitamin D (VD) level due to disturbed trophoblast invasion and failure of spiral artery remodeling. The metabolism of VD is regularized by it signaling molecules expressed by the placenta during pregnancy. Therefore, this study was designed to assess and compare the levels of VD and it signaling molecules in placentae from normotensive and preeclamptic pregnancies and their correlation with spiral artery remodeling.Methods: This study was carried out at Department of Anatomy at Liaquat University of Medical & Health Sciences, Jamshoro after ethical approval on placentae of 122 parturients; 61 from normal and 61 from preeclampsia, data was collected on predesigned proforma and was analyzed on SPSS 23.Results: The mean and standard deviation of maternal age, gestational age, and parity was 32.73±5.9 years, 37.3±3.6 weeks and 3±1 respectively. The wall thickness of SA and VD when compared in two groups found statically significant. Vitamin D signaling molecules were determined by immunostaining compared in two groups by applying Mann Whitney U test and Pearson’s correlation which reveals significant differences in preeclamptic versus controls.Conclusions: Despite extensive research indicating a link between low levels of VD and its signaling molecules in the context of inadequate spiral artery remodeling, there is still a need for further investigation to fully understand the mechanisms underlying this association in preeclampsia.Keywords: Preeclampsia; Remodeling; Spiral artery; Vitamin D; Vitamin D signaling molecules 

Placental genetic variations in vitamin D metabolism and birthweight.

INTRODUCTION: Vitamin D has pleiotropic functions that regulate fetal growth and development. We investigated associations of common placental genetic variations in vitamin D metabolism with birthweight. METHODS: The study was conducted among participants (506 maternal-infant pairs) of a pregnancy cohort study. Data were collected using interviewer-administered questionnaires and post-delivery medical record abstraction. DNA, extracted from placental samples collected at delivery, was genotyped for eight single nucleotide polymorphisms (SNPs) in five vitamin D metabolism genes (CUBN, LRP2, VDR, GC, and CYP2R1). Linear and logistic regression models were used to evaluate associations of SNPs with birthweight and risk of low birthweight, respectively. Effect modification of associations by infant sex was examined using stratified analyses and interaction terms in regression models. RESULTS: Mean (standard-deviation) birthweight among all, male, and female infants was 3482.1 (549.9), 3544.6 (579.0) and 3419.2 (512.5) grams, respectively. Each copy of the minor allele of rs2282679 (GC) was associated with a 68.6 g (95%CI:3.1134.7 g) increase in birthweight overall. Sex-specific associations were observed for SNP rs4667591 (LRP2) (p-value for interaction \u3c 0.001). Each copy of the minor allele of rs4667591 was associated with a 124.7 g (95%CI:20.1229.0 g) increase in birthweight among female infants, and a suggested 81.6 g decrease in birthweight among male infants (95%CI:-183.7,20.5 g). DISCUSSION: Our study identified overall and sex-specific associations between placental genetic variations in vitamin D metabolism and birthweight. If confirmed by larger replication studies, observed associations may provide insight into mechanistic underpinnings of the relationships between placental vitamin D metabolism and birth size

Preeclampsia risk, maternal 25-hydroxyvitamin D concentration, and variation in vitamin D metabolism pathway genes

OBJECTIVE: Our objectives were to study the relationships between 25-hydroxyvitamin D (25(OH)D) and preeclampsia risk, maternal genetic variation in 3 vitamin D metabolism genes (GC, CYP27B1, VDR) and preeclampsia risk, and variation in the same genes and 25(OH)D. METHODS: We used two racially diverse pregnancy cohorts (EVITA and Collaborative Perinatal Project (CPP)) to achieve these objectives. We estimated the association between log-transformed 25(OH)D and preeclampsia risk in EVITA by using log-binomial regression with restricted cubic splines. In EVITA and CPP, we used multivariable logistic and linear regression models to estimate the associations between allelic variation and preeclampsia risk, and genotype and log-transformed 25(OH)D, respectively. Meta-analyses were conducted to calculate estimates of association between and within cohorts. RESULTS: Dose-response associations of 25(OH)D were observed for both severe and mild preeclampsia. Trends of associations were observed in genetic variation and preeclampsia risk. Compared with major allele carriers, Black mothers in EVITA who carried the minor allele for rs11732451 GC single nucleotide polymorphism (SNP) and 2 VDR SNPs (rs4340112, rs10459217) had increased odds of preeclampsia, while the odds were lowered for those who carried the minor allele for 1 GC SNP (rs1099028) and 2 VDR SNPs(rs757344, rs12721364). In the meta-analysis, two VDR SNPs (rs886441 and rs2853561) had trends of decreased odds of preeclampsia for all Black mothers. For the 25(OH)D analysis, statistically significant associations were observed. Compared with those with major allele genotypes, mothers with minor allele genotypes of rs1844885 (GC) and rs11168275 (VDR) had increased 25(OH)D and of rs11732451 (GC) had lowered 25(OH)D. In the meta-analysis on all Black mothers, rs1844885 (GC) was associated with increased 25(OH)D while there was a trend of decreased 25(OH)D for rs10877016 (CYP27B1). CONCLUSIONS: Low 25(OH)D may be enough to reduce risk of preeclampsia. If our findings are confirmed in a replication study, genetic variation may be an independent risk factor for maternal 25(OH)D, making the findings of this research relevant to public health

The Role of Vitamin D Receptors in Gastric epithelial Homeostasis

The gastric epithelium consists of different types of cells, which are involved in gastric homeostasis by balancing cell proliferation and differentiation. This process involves several signaling molecules such as growth factors, hormones and vitamins. Vitamin D3 (VD3) is engaged in several biological activities. It plays a role in cell differentiation, cell proliferation, immune response and also regulates calcium homeostasis. The biological activities of VD3 are mediated by vitamin D receptor (VDR). Target tissues of VD3 in the gastrointestinal tract were identified earlier in intestine, colon and gastric cancer tissues; however, the normal expression of VDR in stomach is poorly studied. So, the main objectives of this thesis are: 1) to investigate the normal expression, distribution and cellular localization of VDR in gastric epithelium and 2) to study possible role of VDR and VD3 in maintaining gastric stem cells proliferation and differentiation by establishing and analyzing mouse model deficient in VD3. Polymerase chain reaction (PCR) analysis showed that VDR as well as enzymes involved in VD3 metabolism are expressed in the different region of normal mouse stomach. Co-immunostaining analysis showed specific expression of VDR in the acid secreting parietal cells and the different mucus secreting cells. The results suggested that parietal cells and mucous cells are targets for VD3 signaling. To examine the role of VD3 on gastric homeostasis, wild type mice were put on VD3 deficient diet for 3 months. Using Real-Time Polymerase Chain Reaction (Real-Time PCR), stomachs of mice deficient of vitamin D showed significant decrease in expression of parietal cell specific genes (HKα and HKβ) and increase gastrin gene expression. Moreover, quantification for cells in the S-phase of the cell cycle showed significant increase in their number in vitamin D deficient mice compared to controls. Gene expression analysis of VDR signaling genes showed significant decrease in PTHLH, but not other target genes like TRPV6 and p21. This work will add value to the field of stomach biology by providing better understanding of how VD3 and VDR are involved in maintaining gastric epithelial homeostasis and how that is related to some stomach conditions such as low gastric acidity and gastric cancer

Vitamin D, the placenta and early pregnancy:effects on trophoblast function

Pregnancy is associated with significant changes in vitamin D metabolism, notably increased maternal serum levels of active vitamin D, 1,25-dihydroxyvitamin (1,25(OH)2D). This appears to be due primarily to increased renal activity of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) that catalyzes synthesis of 1,25(OH)2D, but CYP27B1 expression is also prominent in both the maternal decidua and fetal trophoblast components of the placenta. The precise function of placental synthesis of 1,25(OH)2D remains unclear, but is likely to involve localised tissue-specific responses with both decidua and trophoblast also expressing the vitamin D receptor (VDR) for 1,25(OH)2D. We have previously described immunomodulatory responses to 1,25(OH)2D by diverse populations of VDR-expressing cells within the decidua. The aim of the current review is to detail the role of vitamin D in pregnancy from a trophoblast perspective, with particular emphasis on the potential role of 1,25(OH)2D as a regulator of trophoblast invasion in early pregnancy. Vitamin D-deficiency is common in pregnant women, and a wide range of studies have linked low vitamin D status to adverse events in pregnancy. To date most of these studies have focused on adverse events later in pregnancy, but the current review will explore the potential impact of vitamin D on early pregnancy, and how this may influence implantation and miscarriage

Role of Placental VDR Expression and Function in Common Late Pregnancy Disorders

Vitamin D, besides its classical role in bone metabolism, plays a distinct role in multiple pathways of the feto-maternal unit. Calcitriol is the major active ligand of the nuclear vitamin D receptor (VDR). The vitamin D receptor (VDR) is expressed in different uteroplacental parts and exerts a variety of functions in physiologic pregnancy. It regulates decidualisation and implantation, influences hormone secretion and placental immune modulations. This review highlights the role of the vitamin D receptor in physiologic and disturbed pregnancy, as preeclampsia, fetal growth restriction, gestational diabetes and preterm birth. We discuss the existing literature regarding common VDR polymorphisms in these pregnancy disorders

Preeclampsia

Preeclampsia is a disorder of pregnancy characterized by high blood pressure, edema, and proteinuria that affects 2%–8% of pregnancies worldwide. Hypertensive disorders of pregnancy, including preeclampsia, are among the most common causes of death in pregnant persons. Over six chapters, this book examines the pathophysiology of preeclampsia, vitamin D deficiency as a risk factor for preeclampsia, the cellular changes that occur with preeclampsia, associated organ dysfunction, gestational endotheliopathy, and ophthalmic complications of preeclampsia

Immunomodulatory Effects of Vitamin D in Pregnancy and Beyond.

In addition to its role in calcium homeostasis and bone formation, a modulatory role of the active form of vitamin D on cells of the immune system, particularly T lymphocytes, has been described. The effects of vitamin D on the production and action of several cytokines has been intensively investigated in recent years. In this connection, deficiency of vitamin D has been associated with several autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Hashimoto Thyroiditis (HT), and multiple sclerosis (MS). In a successful pregnancy, the maternal immune response needs to adapt to accommodate the semiallogeneic fetus. Disturbances in maternal tolerance are implicated in infertility and pregnancy complications such as miscarriages (RM) and preeclampsia (PE). It is well-known that a subset of T lymphocytes, regulatory T cells (Tregs) exhibit potent suppressive activity, and have a crucial role in curtailing the destructive response of the immune system during pregnancy, and preventing autoimmune diseases. Interestingly, vitamin D deficiency is common in pregnant women, despite the widespread use of prenatal vitamins, and adverse pregnancy outcomes such as RM, PE, intrauterine growth restriction have been linked to hypovitaminosis D during pregnancy. Research has shown that autoimmune diseases have a significant prevalence within the female population, and women with autoimmune disorders are at higher risk for adverse pregnancy outcomes. Provocatively, dysregulation of T cells plays a crucial role in the pathogenesis of autoimmunity, and adverse pregnancy outcomes where these pathologies are also associated with vitamin D deficiency. This article reviews the immunomodulatory role of vitamin D in autoimmune diseases and pregnancy. In particular, we will describe the role of vitamin D from conception until delivery, including the health of the offspring. This review highlights an observational study where hypovitaminosis D was correlated with decreased fertility, increased disease activity, placental insufficiency, and preeclampsia in women with APS

Vitamin D and intrauterine growth restriction: a cross-sectional study

Vitamin D plays a critical role in maintaining bone health, regulating calcium homeostasis, and modulating immune responses. During pregnancy, it supports fetal bone mineralization and proper placental function. Deficiency in vitamin D can impair calcium absorption, disrupt placental function, and lead to adverse outcomes like intrauterine growth restriction (IUGR). Despite abundant sunlight, vitamin D deficiency is highly prevalent in countries like Indonesia. This study evaluates the relationship between maternal vitamin D levels and IUGR risk while considering additional factors like placental function and calcium metabolism. In this cross-sectional study, 60 patients, 30 with IUGR and 30 without, were included. Vitamin D levels were measured using the enzyme-linked immunosorbent assay, and statistical analysis compared the IUGR and non-IUGR groups. Baseline data [age, body mass index (BMI), placental inflammation, preeclampsia status] were analyzed using Chi-square and Mann-Whitney tests. Statistical significance was set at p<0.05, using IBM SPSS 24 (IL, USA). A significant association between maternal factors and IUGR was found. Higher BMI (≥25 kg/m2) and placental inflammation were more prevalent in the IUGR group. Vitamin D deficiency was strongly linked to IUGR, with 90% of IUGR cases showing deficient levels. The IUGR group had significantly lower vitamin D levels (13.84 ng/mL versus 25.93 ng/mL), with a strong inverse correlation (r=-0.86, p=0.00). This study shows a strong link between maternal vitamin D deficiency and increased IUGR risk, emphasizing its role in placental function and fetal development

Vitamin D in pregnancy: understanding immune effects in the decidua

Epidemiology has linked preeclampsia (PET) to vitamin D deficiency. To date, studies have focused upon serum 25-hydroxyvitamin D3 (25(0H. )D3) alone as the marker of vitamin D status.~We provide strong evidence comprehensive analysis of vitamin D metabolites in pregnancy is highly informative, particularly within the context of PET. Uniquely, analysis of maternal urinary metabolites provides a novel insight into vitamin D and the kidney, with lower 25(0H)D3 and 24,25(0H)2D3 excretion early indicators of a predisposition towards PET. Since vitamin D is a potent regulator of immune function, and the decidua appears a key extra-renal site for vitamin D metabolism, we investigated effects of 1 ,25(0H)2D3 upon decidual uterine natural killer cells and macrophages. We show both express a functional vitamin-D system and demonstrate differential sensitivity to 1 ,25(0H)2D3 compared to their peripheral counterparts. To understand the functional impact of vitamin D, whole transcriptomic analysis of 1,25(0H)2D3-mediated effects upon uNK and macrophages was performed. We show the actions of vitamin D extend far beyond simple immuno-regulation, targeting major cellular functions including migration, adhesion and apoptosis. In particular, our data support effects highly relevant to decidualisation. We anticipate these findings to be highly relevant within the context of vitamin D deficiency, mal placentation and PET