Maternal vitamin D deficiency influences long-chain polyunsaturated fatty acids and pregnancy outcome in association with alterations in one-carbon metabolism.

Preeclampsia is a pregnancy-specific disorder, leading to maternal and infant morbidity and mortality. Abnormal placentation has been reported in preeclampsia. Nutrients like vitamin D and long-chain polyunsaturated fatty acids (LCPUFA) are known to play a role in placental development. In an animal model, we have previously demonstrated that maternal vitamin D deficiency increases the thromboxane/prostacyclin ratio and contributes to inflammation and vasoconstriction. We hypothesize that maternal vitamin D status influences placental LCPUFA metabolism through alterations in one carbon metabolism in women with preeclampsia. To test this hypothesis, we recruited 69 normotensive control (NC) women and 50 women with preeclampsia. Women with preeclampsia had lower placental protein and mRNA levels of cystathionine-ß-synthase (CBS), higher plasma malondialdehyde (MDA) levels and higher levels of arachidonic acid (AA) and total omega-6 fatty acids in the placenta. Women with preeclampsia also demonstrated higher placental mRNA levels of cyclooxygenase-2 (COX-2) as compared to NC women. Maternal 25(OH)D levels were negatively associated with maternal plasma MDA levels. Placental vitamin D receptor (VDR) levels were positively associated with CBS while maternal MDA levels were positively associated with serum levels of thromboxane-B2 (TXB2) levels. Our findings indicate that vitamin D deficiency increases oxidative stress through alterations in one carbon metabolism to influence pro-inflammatory omega-6 metabolic pathway in the placenta. This study demonstrates a possible mechanism through which vitamin D deficiency can result in an imbalance in the LCPUFA metabolites and contribute to placental inflammation and endothelial dysfunction in preeclampsia.

Maternal vitamin D deficiency increases the thromboxane/prostacyclin ratio through alterations in the one-carbon cycle in Wistar rats.

This study aims to test the hypothesis that vitamin D deficiency can influence long-chain polyunsaturated fatty acid metabolism through alterations in the one-carbon cycle. Wistar rats (n = 8 per group) were given either a control (1,000 IU D3/kg diet) or a vitamin D deficient (VDD) (0 IU D3/kg diet) diet from pre-pregnancy to delivery. On day 20 of gestation, pregnant female rats were delivered by C-section to collect placenta and blood. VDD group demonstrated high serum parathyroid hormone, low serum phosphate, low plasma folate, higher plasma homocysteine, and higher plasma malondialdehyde levels (P < 0.05 for all) as compared to control. Lower protein levels of placental cystathionine-ß-synthase enzyme (P < 0.05) were observed in the VDD group as compared to control. VDD group demonstrated higher placental mRNA levels of the enzymes phospholipase A2 and cyclooxygenase-2 (P < 0.05 for both) as compared to control. Protein levels of the enzymes phospholipase A2 and cyclooxygenase-2 were lower (P < 0.05 for both) in the VDD group as compared to the control group. The ratio of thromboxane B2 and 6-keto prostaglandin F1α in serum was higher (P < 0.05) in the VDD group as compared to control; although the serum levels of 6-keto prostaglandin F1α and thromboxane B2 were similar in both the groups. Our findings suggest that increased oxidative stress due to maternal vitamin D deficiency results in the imbalance between the vasoconstrictor (thromboxane B2 ) and vasodilator (6-keto prostaglandin F1α ) eicosanoids, which may lead to endothelial dysfunction and poor pregnancy outcome. © 2019 BioFactors, 45 (4):548-555, 2019.

Altered metabolic homeostasis between vitamin D and long chain polyunsaturated fatty acids in preeclampsia.

Sub-optimal maternal nutrition may result in pregnancy complications like preeclampsia. Preeclampsia is known to be of placental origin and a major cause of maternal morbidity and mortality worldwide. Our earlier studies suggest that altered metabolism of folic acid, vitamin B12 and long chain polyunsaturated fatty acid (LCPUFAs) in the one carbon cycle increases homocysteine levels in preeclampsia. Recent reports indicate that vitamin D deficiency may also have a role in preeclampsia, although the mechanisms are unclear. A disturbed one carbon cycle can influence methylation patterns of various genes involved in placental development. Altered expression of cystathionine beta synthase (CBS) gene can result in hyperhomocystenemia. Higher homocysteine levels are known to increase reactive oxygen species (ROS) production which in turn leads to increased expression of phospholipase A2 (PLA2) and cyclooxygenase-2 (COX-2). Higher expression of PLA2 and COX-2 can influence the release of arachidonic acid (AA) from membrane phospholipid and result in increased conversion to thromboxane. Vitamin D [1,25(OH)2D3] is known to induce the CBS gene expression while it can suppress the oxidative stress-induced COX-2 up-regulation and thromboxane production. Based on this, we propose a novel hypothesis that a disturbed vitamin D and LCPUFA metabolism influence the regulation of the one carbon cycle which will trigger inflammation through oxidative stress in preeclampsia. This may lead to altered feto-placental growth and development in preeclampsia.