Pregnancy: The extraordinary metabolism of vitamin D
The placenta plays an important role in how vitamin D is metabolized and supplied to the fetus.
- Division of Neonatology, Shawn Jenkins Children’s Hospital, United States
- Darby Children’s Research Institute, Medical University of South Carolina, United States
Vitamin D helps the intestine to absorb calcium and other minerals that the body needs, and provides support to the immune system. To carry out these roles, vitamin D must be converted into the active hormone calcitriol (also known as 1,25-dihydroxy-vitamin D). First, vitamin D is metabolized by the liver into a compound called 25(OH)D, which then is broken down into its active form calcitriol, mainly in the kidneys. This metabolic process is tightly regulated and relies on calcium and various hormones, including calcitriol itself (Pike and Christakos, 2017).
In 1979, it was discovered that the level of calcitriol circulating in the blood is elevated during pregnancy (Kumar et al., 1979). This massive increase occurs at the start of pregnancy following the implantation of the placenta (Hollis et al., 2011). However, how and why the metabolism of vitamin D changes so drastically during the early stages of pregnancy is not fully understood.
It was initially assumed that the rising levels of calcitriol were generated in the maternal kidneys, where the key enzyme that metabolizes vitamin D is located (Kumar et al., 1979). However, further studies discovered that this active hormone could also be produced outside the kidneys, bringing into question where this excess of calcitriol is coming from (Gray et al., 1981).
The growing fetus cannot synthesize its own vitamin D, and relies on the placenta to transfer the metabolite 25(OH)D from the maternal bloodstream. This compound was thought to pass into the fetus by passively diffusing across the placenta (Greer et al., 1984; Hollis and Wagner, 2013). Now, in eLife, Jane Cleal from the University of Southampton and co-workers – including Brogan Ashley and Claire Simner as joint first authors – report that the amount of vitamin D the fetus receives is actually regulated by the placenta actively taking up and breaking down 25(OH)D (Ashley et al., 2022).
The team (who are based in various institutes in the United Kingdom and the United States) used two new model systems to study how vitamin D metabolites are regulated in the placenta. First, they built a perfusion model using a structure from the placenta, and flowed it with fluids that mimic how blood circulates from the maternal bloodstream to the fetus. Using this set-up, Ashley, Simner et al. were able to infuse vitamin D metabolites into the bloodstream on the maternal side of the structure, and track the amount that was transferred to the placenta and fetal circulation. In addition to this, the team employed various commonly used techniques to explore the effect vitamin D had on fragments of placenta tissue grown in the laboratory.
These models led to the identification of a mechanism that actively uptakes 25(OH)D on the maternal-facing side of the placenta. Once inside, 25(OH)D is further metabolized to calcitriol, where it imparts impressive alterations on specific placental genes. This influences the level of 25(OH)D and its metabolites in both the fetal and maternal circulation.
These findings suggest that the metabolism of 25(OH)D by the placenta may contribute to the increased level of calcitriol observed in the maternal bloodstream during pregnancy. However, these metabolic changes can only account for a small portion of the excess calcitriol detected. Indeed, a previous study found that a pregnant woman whose kidneys could not metabolize vitamin D only experienced a small increase in calcitriol, despite the placenta and the kidneys of the fetus functioning normally (Greer et al., 1984). This suggests that the placenta only contributes a marginal amount of the calcitriol found in the blood during pregnancy, with the maternal kidneys producing the large majority of the excess.
Further experiments using the model systems revealed that 25(OH)D altered the expression of genes and proteins involved in cellular pathways which are critical for the placenta’s role in pregnancy. This is in keeping with an earlier study which showed a significant association between maternal vitamin D levels and the expression of two placenta proteins linked to pre-eclampsia, a condition that causes vascular changes, high blood pressure and abnormal kidney function during pregnancy (Schulz et al., 2017).
Ashley, Simner et al. also found that vitamin D induced epigenetic changes that reshaped how the placenta responded to this compound and its metabolites. This is similar to a previous study in which vitamin D supplements provided during pregnancy reduced the epigenetic changes associated with gestational aging (Chen et al., 2020).
Vitamin D may be pivotal to the function of the placenta, thereby affecting both maternal and fetal health. As such, the work by Ashley, Simner et al. raises important questions about the role this compound plays during pregnancy. Initially vitamin D was thought to only be involved in maintaining calcium levels; however, this study and others suggest it is also important for modifying the immune response of the fetus (Mirzakhani et al., 2016; Khatiwada et al., 2021; Zahran et al., 2018).
Various other questions about the metabolism of vitamin D also remain unanswered. For example, how are such high amounts of calcitriol tolerated during pregnancy, including by the fetus, which would normally lead to fatal levels of calcium? And how does the enzyme in the maternal kidneys, which is highly regulated, lose control and produce such ‘toxic’ amounts of calcitriol? Investigating these questions, as well as others, will provide new insights into how vitamin D metabolism is controlled during pregnancy and will further our understanding of its role in optimizing maternal and fetal health.
References
-
Vitamin D and pregnancy: the maternal-fetal metabolism of vitamin DEndocrine Reviews 2:264–274.https://doi.org/10.1210/edrv-2-3-264
-
Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectivenessJournal of Bone and Mineral Research 26:2341–2357.https://doi.org/10.1002/jbmr.463
-
Clinical review: The role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomesThe Journal of Clinical Endocrinology and Metabolism 98:4619–4628.https://doi.org/10.1210/jc.2013-2653
-
Elevated 1,25-dihydroxyvitamin D plasma levels in normal human pregnancy and lactationThe Journal of Clinical Investigation 63:342–344.https://doi.org/10.1172/JCI109308
-
Early pregnancy vitamin D status and risk of preeclampsiaThe Journal of Clinical Investigation 126:4702–4715.https://doi.org/10.1172/JCI89031
-
Biology and mechanisms of action of the vitamin D hormoneEndocrinology and Metabolism Clinics of North America 46:815–843.https://doi.org/10.1016/j.ecl.2017.07.001
-
Maternal vitamin D sufficiency and reduced placental gene expression in angiogenic biomarkers related to comorbidities of pregnancyThe Journal of Steroid Biochemistry and Molecular Biology 173:273–279.https://doi.org/10.1016/j.jsbmb.2017.02.003
-
Significant correlation between regulatory T cells and vitamin D status in term and preterm laborJournal of Reproductive Immunology 129:15–22.https://doi.org/10.1016/j.jri.2018.07.004
Article and author information
Author details
Publication history
- Version of Record published: March 8, 2022 (version 1)
Copyright
© 2022, Wagner and Hollis
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,563
- views
-
- 165
- downloads
-
- 6
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Pregnancy: The extraordinary metabolism of vitamin D
eLife 11:e77539.
https://doi.org/10.7554/eLife.77539
Further reading
-
- Cell Biology
- Developmental Biology
During Caenorhabditis elegans development, multiple cells migrate long distances or extend processes to reach their final position and/or attain proper shape. The Wnt signalling pathway stands out as one of the major coordinators of cell migration or cell outgrowth along the anterior-posterior body axis. The outcome of Wnt signalling is fine-tuned by various mechanisms including endocytosis. In this study, we show that SEL-5, the C. elegans orthologue of mammalian AP2-associated kinase AAK1, acts together with the retromer complex as a positive regulator of EGL-20/Wnt signalling during the migration of QL neuroblast daughter cells. At the same time, SEL-5 in cooperation with the retromer complex is also required during excretory canal cell outgrowth. Importantly, SEL-5 kinase activity is not required for its role in neuronal migration or excretory cell outgrowth, and neither of these processes is dependent on DPY-23/AP2M1 phosphorylation. We further establish that the Wnt proteins CWN-1 and CWN-2 together with the Frizzled receptor CFZ-2 positively regulate excretory cell outgrowth, while LIN-44/Wnt and LIN-17/Frizzled together generate a stop signal inhibiting its extension.
-
- Developmental Biology
Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries and play a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular disease and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating dedifferentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that arterial specification of CoW endothelial cells (ECs) occurs after their migration from cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors after they were recruited to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity and wall shear stress. Furthermore, pulsatile flow induces differentiation of human brain PDGFRB+ mural cells into VSMCs, and blood flow is required for VSMC differentiation on zebrafish CoW arteries. Consistently, flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, and klf2a knockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight blood flow activation of endothelial klf2a as a mechanism regulating initial VSMC differentiation on vertebrate brain arteries.
