Dietary Vitamin D Restriction in Pregnant Female Mice Is Associated With Maternal Hypertension and Altered Placental and Fetal Development

Abstract

Epidemiology has linked vitamin D deficiency with preeclampsia in humans. We hypothesized that low vitamin D status in pregnant mice may lead to symptoms of preeclampsia. Female BL6 mice were raised on vitamin D-sufficient or -deficient diets from weeks 4 of age and then mated with vitamin D-sufficient BL6 males at week 8. The resulting pregnant mice were either allowed to deliver pups and monitored for blood pressure (BP) and weight of offspring or euthanized at day 14 or 18 of gestation (E14 or E18) for analysis of serum, placental/kidney tissues, and fetuses. At E14 serum concentrations of 25-hydroxyvitamin D (30.1 Ϯ 5.0 vs 1.8 Ϯ 0.6 ng/mL, P Ͻ .001) and 1,25-dihydroxyvitamin D (119.5 Ϯ 18.7 vs 37.4 Ϯ 5.1 pg/mL, P Ͻ .01) were higher in sufficient vs deficient pregnant mice. At E14 BP was significantly elevated in vitamin D-deficient pregnant mice relative to vitamin D-sufficient mice for both systolic BP (124.89 Ϯ 2.28 vs 105.34 Ϯ 3.61 mm Hg, P Ͻ .001) and mean arterial pressure (115.33 Ϯ 1.93 vs 89.33 Ϯ 5.02 mm Hg, P Ͻ .001). This elevation continued through pregnancy until 7 days postpartum (PP7) but returned to baseline by PP14. Analysis of maternal kidneys showed increased expression of mRNA for renin and the angiotensin II receptor (3-and 4-fold, respectively) in vitamin D-deficient vs -sufficient mice at E14. Histological analysis of E14 placentas from vitamin D-deficient mice showed decreased vascular diameter within the labyrinth region. E14 and E18 fetuses from vitamin D-deficient mice were larger than those from vitamin D-sufficient mothers. However, by PP14 pups from vitamin D-deficient mothers weighed significantly less than those from vitamin D-sufficient mothers. Resupplementation of vitamin D periconceptually partially reversed the effects of vitamin D deficiency. These data provide further evidence that low vitamin D status may predispose pregnant women to dysregulated placental development and elevated blood pressure. (Endocrinology 154: 2270 -2280, 2013) P reeclampsia, typically characterized by maternal hypertension, proteinuria, and a variation of other signs and symptoms, is a leading cause of preterm delivery. Preeclampsia complicates up to 10% of all pregnancies, 3% severely with potential life-threatening consequences (1). Impaired vitamin D status appears to be prevalent among pregnant women in general (2), and epidemiology suggests that there is a link between vitamin D insufficiency and preeclampsia (3-5). A longitudinal study of 697 pregnant women showed an increased incidence of preeclampsia with lower maternal vitamin D levels measured at 24 -26 weeks' gestation (6). Likewise, a retrospective analysis of

Characterization of an animal model of pregnancy-induced vitamin D deficiency due to metabolic gene dysregulation

“…In addition, we propose that BN rats can be a useful model to investigate the molecular and physiological roles of vitamin D during mammalian pregnancy. Recent studies have suggested that vitamin D effects in mammalian pregnancy include the regulation of the immune, endocrine, and cardiovascular systems (2,3,30,31,39) warranting further researc.…”

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

“…No mention was made as to whether maternal vitamin D deficiency led to a reduced conception rate, and no measurements of bone mass or mineralization were performed. The placentas from vitamin D-deficient pregnancies were of identical weight but had smaller diameters, and histological evidence of reduced vascular diameters within the labyrinthine placenta, compared with pregnancies from vitamin D-sufficient mothers (563).…”

“…Nonskeletal outcomes of pregnancy have received little attention in these animal studies, but the recent study of vitamin D-deficient mice found higher systolic and diastolic blood pressure, and upregulation of renal expression of renin and angiotensin II receptor mRNA, compared with vitamin D-sufficient mice (563). These findings support the possibility that vitamin D deficiency may increase the risk of pregnancy-induced hypertension.…”

“…More recently, severe vitamin D deficiency has been studied in mice, which had identical litter sizes but bore pups of modestly greater weights and slightly increased lengths, compared with vitamin D-sufficient mothers (563). The diet was deficient in vitamin D but not enriched in calcium.…”

Immunological role of vitamin D at the maternal–fetal interface

“…In studies using partially purified uNK cells from first-trimester human pregnancies, treatment with either 25OHD or 1,25(OH) 2 D ex vivo promoted antibacterial and anti-inflammatory responses (Evans et al 2006). In view of the fact that vitamin D deficiency in humans (Bodnar et al 2007b) and mice (Liu et al 2013) has been linked to PET, it is interesting to speculate that uNK cells may play a role in the pathophysiology of this complication of pregnancy. uNK cells appear to play a pivotal role in spiral arteriole remodelling (Robson et al 2012) and the regulation of extravillous trophoblast invasion into decidua basalis and superficial myometrium through the production of local cytokines and chemokines (Lash et al 2010b).…”