Dietary vitamin D restriction in pregnant female mice is associated with maternal hypertension and altered placental and fetal development

摘要

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 ± 5.0 vs 1.8 ± 0.6 ng/mL, P < .001) and 1,25-dihydroxyvitamin D (119.5 ± 18.7 vs 37.4 ± 5.1 pg/mL, P < .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 ± 2.28 vs 105.34 ± 3.61 mm Hg, P < .001) and mean arterial pressure (115.33 ± 1.93 vs 89.33 ± 5.02 mm Hg, P < .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.