Vitamin D - roles in women's reproductive health?

In the past few years a growing interest in vitamin D can be observed in the lay and biomedical literature due to findings demonstrating a low vitamin D status in the population. In addition to its importance for the regulation of calcium and phosphorus homeostasis recent epidemiologic studies have observed relationships between low vitamin D levels and multiple disease states. This secosteroid hormone also regulates the expression of a large number of genes in reproductive tissues implicating a role for vitamin D in female reproduction. In this report we summarize the recent evidence that vitamin D status influences female reproductive and pregnancy outcomes. Human and animal data suggest that low vitamin D status is associated with impaired fertility, endometriosis and polycystic ovary syndrome. Evidence from observational studies shows higher rates of preeclampsia, preterm birth, bacterial vaginosis and gestational diabetes in women with low vitamin D levels. However, confirmation of experimental observations establishing an association of vitamin D deficiency with adverse reproductive outcomes by high quality observational and large-scale randomized clinical trials is still lacking. The determination of optimal 25(OH)D3 levels in the reproductive period and the amount of vitamin D supplementation required to achieve those levels for the numerous actions of vitamin D throughout a woman's life would have important public health implications

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Vitamin D antagonizes negative effects of preeclampsia on fetal endothelial colony forming cell number and function

Context: Endothelial dysfunction is a primary feature of preeclampsia, a pregnancy complication associated with an increased future cardiovascular risk for mother and offspring. Endothelial colony forming cells (ECFC) are endothelial progenitor cells that participate in vasculogenesis and endothelial repair. Objective: We hypothesized that the number and functional properties of fetal cord blood-derived ECFCs are reduced in preeclampsia compared to uncomplicated pregnancy (controls), and asked if adverse effects of preeclampsia on ECFC function are reversed by 1,25 (OH)2 vitamin D3. Design, Setting, Patients: This was a nested, case-control study. Forty women with uncomplicated pregnancy and 33 women with PE were recruited at Magee-Womens Hospital (USA) or at Hannover Medical School (Germany). Main Outcome Measures: Time to ECFC colony appearance in culture, and number of colonies formed, were determined. Functional abilities of ECFCs were assessed in vitro by tubule formation in Matrigel assay, migration, and proliferation. ECFC function was tested in the presence or absence of 1,25 (OH)2 vitamin D 3, and after vitamin D receptor (VDR) or VEGF signaling blockade. Results: The number of cord ECFC colonies was lower (P = 0.04) in preeclampsia compared to controls. ECFCs from preeclampsia showed reduced proliferation (P<0.0001), formed fewer tubules (P = 0.02), and migrated less (P = 0.049) than control. Vitamin D3 significantly improved preeclampsia ECFC functional properties. VDR- or VEGF blockade reduced tubule formation, partially restorable by vitamin D3. Conclusion: Fetal ECFCs from preeclamptic pregnancies are reduced in number and dysfunctional. Vitamin D3 had rescuing effects. This may have implications for the increased cardiovascular risk associated with preeclampsia. © 2014 von Versen-Höynck et al

Preeclampsia-Associated Alteration of DNA Methylation in Fetal Endothelial Progenitor Cells

ObjectiveThe pregnancy complication preeclampsia represents an independent risk factor for cardiovascular disease. Our previous research shows a diminished function of fetal endothelial colony-forming cells (ECFC), a proliferative subgroup of endothelial progenitor cells (EPC) in preeclampsia. The aim of this study was to further investigate whether DNA methylation of fetal EPC is affected in preeclampsia.MethodsThe genomic methylation pattern of fetal ECFC from uncomplicated and preeclamptic pregnancies was compared for 865918 CpG sites, and genes were classified into gene networks. Low and advanced cell culture passages were compared to explore whether expansion of fetal ECFC in cell culture leads to changes in global methylation status and if methylation characteristics in preeclampsia are maintained with increasing passage.ResultsA differential methylation pattern of fetal ECFC from preeclampsia compared to uncomplicated pregnancy was detected for a total of 1266 CpG sites in passage 3, and for 2362 sites in passage 5. Key features of primary networks implicated by methylation differences included cell metabolism, cell cycle and transcription and, more specifically, genes involved in cell-cell interaction and Wnt signaling. We identified an overlap between differentially regulated pathways in preeclampsia and cardiovascular system development and function. Cell culture passages 3 and 5 showed similar gene network profiles, and 1260 out of 1266 preeclampsia-associated methylation changes detected in passage 3 were confirmed in passage 5.ConclusionMethylation modification caused by preeclampsia is stable and detectable even in higher cell culture passages. An epigenetically modified endothelial precursor may influence both normal morphogenesis and postnatal vascular repair capacity. Further studies on epigenetic modifications in complicated pregnancies are needed to facilitate development of EPC based therapies for cardiovascular alterations

Vitamin D depletion aggravates hypertension and target-organ damage

BACKGROUND: We tested the controversial hypothesis that vitamin D depletion aggravates hypertension and target-organ damage by influencing renin. METHODS AND RESULTS: Four-week-old double-transgenic rats (dTGR) with excess angiotensin (Ang) II production due to overexpression of the human renin (hREN) and angiotensinogen (hAGT) genes received vitamin D-depleted (n=18) or standard chow (n=15) for 3 weeks. The depleted group had very low serum 25-hydroxyvitamin D levels (mean+/-SEM; 3.8+/-0.29 versus 40.6+/-1.19 nmol/L) and had higher mean systolic BP at week 5 (158+/-3.5 versus 134.6+/-3.7 mm Hg, P<0.001), week 6 (176.6+/-3.3 versus 162.3+/-3.8 mm Hg, P<0.01), and week 7 (171.6+/-5.1 versus 155.9+/-4.3 mm Hg, P<0.05). Vitamin D depletion led to increased relative heart weights and increased serum creatinine concentrations. Furthermore, the mRNAs of natriuretic peptides, neutrophil gelatinase-associated lipocalin, hREN, and rRen were increased by vitamin D depletion. Regulatory T cells in the spleen and in the circulation were not affected. Ang metabolites, including Ang II and the counter-regulatory breakdown product Ang 1 to 7, were significantly up-regulated in the vitamin D-depleted groups, while ACE-1 and ACE-2 activities were not affected. CONCLUSIONS: Short-term severe vitamin D depletion aggravated hypertension and target-organ damage in dTGR. Our data suggest that even short-term severe vitamin D deficiency may directly promote hypertension and impacts on renin-angiotensin system components that could contribute to target-organ damage. The findings add to the evidence that vitamin D deficiency could also affect human hypertension

Prorenin periconceptionally and in pregnancy: Does it have a physiological role?

Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system plays a key role in this adaptation process. One of its components, prorenin, is released in significant amounts from the ovary and uteroplacental unit. This review describes the sources of prorenin in the periconception period and in pregnancy, including its modulation by in-vitro fertilization protocols, and discusses its potential effects, among others focusing on preeclampsia. It ends with discussing the long-term consequences, even in later life, of inappropriate renin-angiotensin-aldosterone system activity in pregnancy and offers directions for future research. Ultimately, a full understanding of the role of prorenin periconceptionally and during pregnancy will help to develop tools to diagnose and/or prevent reproductive complications

Placental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system

Normal placentation occurs under low oxygen tensions yet hypoxia is also implicated in placental pathologies such as pre-eclampsia (PE). Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) are known to promote angiogenesis and vascularisation. We hypothesised that placental adenosine A2AR receptor and HIF-1α would change through pregnancy in association with the RAS. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at ≤10 weeks’ (early TOP) and >10 weeks’ (mid TOP) gestations; at delivery from normotensive (NT) and PE pregnancy. Results were compared to our previously reported data on the angiotensin receptors: AT1R, AT2R and AT4R. Protein expression of both A2AR and HIF-1α was highest in early TOP and positively correlated through pregnancy (P<0.0001): expression was higher in PE than NT at delivery (P<0.0001 for both). The A2AR positively correlated with the AT4R in placentae in early pregnancy (r=0.53; P=0.035), but not in 3rd trimester samples. Our findings suggest a role for adenosine and RAS in promoting placentation and as a potential adaptation to poor placental perfusion in pre-eclampsia

Determinants of Maternal Renin-Angiotensin-Aldosterone-System Activation in Early Pregnancy: Insights From 2 Cohorts

Context: The corpus luteum (CL) secretes prorenin, renin’s inactive precursor. It may thus contribute to the renin-angiotensin-aldosterone-system (RAAS) activation that is required for maternal adaptation in pregnancy. Whether this activation is disturbed in pregnancies lacking a CL is unknown. Objective: The objective of this work is to investigate maternal RAAS determinants in early pregnancy. Design and Setting: Two observational prospective cohort studies took place at 2 tertiary referral hospitals. Patients and Intervention(s): Pregnancies (n = 277) were stratified by CL number and in vitro fertilization (IVF) protocol: 0 CL (programmed cycle frozen embryo transfer [FET], n = 28), 1 CL (natural cycle FET, n = 41 and spontaneous conceptions, n = 139), and more than 1 CL (ovarian stimulation and fresh embryo transfer, n = 69). Methods: Quantification was performed for maternal prorenin, renin, and aldosterone blood levels at 5, 9, and 11 weeks of gestation. Results: Prorenin and renin were lower in the absence of a CL at all time points when compared to 1 CL, whereas prorenin, renin, and aldosterone were higher in the presence of more than 1 CL vs 1 CL (P < .05). Ovarian stimulation with menopausal gonadotropin resulted in higher prorenin, renin, and aldosterone concentrations during the late first trimester than recombinant follicle-stimulating hormone (P < .05). Prorenin, and to a lesser degree renin, correlated positively with serum progesterone and relaxin, but not serum estradiol. Total follicle diameter, body mass index (BMI), polycystic ovary syndrome (PCOS), and antimüllerian hormone (AMH) were additional determinants of circulating prorenin. Finally, pregnancies conceived in the

Vitamin D prevents endothelial progenitor cell dysfunction induced by sera from women with preeclampsia or conditioned media from hypoxic placenta

Context: Placenta-derived circulating factors contribute to the maternal endothelial dysfunction underlying preeclampsia. Endothelial colony forming cells (ECFC), a sub-population of endothelial progenitor cells (EPCs), are thought to be involved in vasculogenesis and endothelial repair. Low vitamin D concentrations are associated with an increased risk for preeclampsia. Objective: We hypothesized that the function of human fetal ECFCs in culture would be suppressed by exposure to preeclampsia-related factors-preeclampsia serum or hypoxic placental conditioned medium- in a fashion reversed by vitamin D. Design, Setting, Patients: ECFCs were isolated from cord blood of uncomplicated pregnancies and expanded in culture. Uncomplicated pregnancy villous placenta in explant culture were exposed to either 2% (hypoxic), 8% (normoxic) or 21% (hyperoxic) O2 for 48 h, after which the conditioned media (CM) was collected. Outcome Measures: ECFC tubule formation (Matrigel assay) and migration were examined in the presence of either maternal serum from preeclampsia cases or uncomplicated pregnancy controls, or pooled CM, in the presence or absence of 1,25(OH)2 vitamin D3. Results: 1,25(OH)2 vitamin D3 reversed the adverse effects of preeclampsia serum or CM from hypoxic placenta on ECFCs capillary-tube formation and migration. Silencing of VDR expression by VDR siRNA, VDR blockade, or VEGF pathway blockade reduced ECFC functional abilities. Effects of VDR or VEGF blockade were partially prevented by vitamin D. Conclusion: Vitamin D promotes the capillary-like tubule formation and migration of ECFCs in culture, minimizing the negative effects of exposure to preeclampsia-related factors. Further evaluation of the role of vitamin D in ECFC regulation and preeclampsia is warranted. © 2014 Brodowski et al