Vitamin D deficiency contribute to the development of preeclampsia through increased sFlt‐1 production and impaired vascular function

Abstract

Preeclampsia (PE) is a pregnancy‐specific syndrome that affects 5~8% pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. Although the underlying mechanism remains unclear, PE is widely accepted to be induced, in part, by uteroplacental ischemia, which leads to increased antiangiogenic factors, such as sFlt‐1, which antagonizes the angiogenic factors, causing widespread vascular dysfunction. Vitamin D deficiency (VDD) is a widespread public health issue, and increasing studies suggested that VDD is a possible risk factor for the development of PE; however, the underlying mechanism that contributes to the increased risk of preeclampsia in vitamin D deficient patients is not clear. We tested the hypothesis that vitamin D deficiency contributes to the development of PE in a placental ischemic rat model by increasing sFlt‐1 production and impairing vascular function. We first induced VDD in Sprague‐Dawley rats (DYET 119273 vs 110842, Dyets Inc., USA) prior to RUPP (Reduced Uterine Perfusion Pressure) surgery on gestational day (GD) 14. Blood pressure was monitored via carotid catheter. On GD19, uterine arteries were harvested to determine vascular reactivity on a wire myograph. We found that RUPP surgery significantly increased mean arterial blood pressure as expected(Ctrl+Sham, n=12, 102±10 mmHg; Ctrl+RUPP, n=12, 117±11 mmHg; P<0.01), and this was significantly enhanced by vitamin D deficiency (VDD+RUPP, n=12, 136±11 mmHg; P<0.01). Plasma sFlt‐1 concentrations were significantly increased in VDD rats (n=12, 117±15 pg/mL) compared to the control group(n=12, 49±17 pg/mL)(P<0.05), and VEGF concentrations were significantly decreased(Ctrl, n=12, 1899±371 pg/mL; VDD, n=6, 1071±249 pg/mL, P<0.05). VDD induced endothelial dysfunction in uterine arteries (% relaxation, control, n=6, 95±7%; VDD, n=6, 37±11%, P<0.05). The circulating biomarkers for endothelial dysfunction also significantly increased. The E‐Selectin increased from 5166±1217 pg/mL to 5756±1053 pg/mL (P<0.05). The ICAM‐1 levels increased from 3.15±1.03 ng/mL to 3.50±0.94 ng/mL (P<0.05). The VCAM‐1 level increased from 44±13 ng/mL to 53±11 ng/mL (p<0.05). These results suggest that vitamin D deficiency contributes to the onset of preeclampsia by increased sFlt‐1 production and impaired vascular function.Support or Funding InformationThis research was supported by the National Natural Science Foundation of China (81601318) and Shandong Province Health and Medical Science and Technology Program (2016WS0668), Weifang Medical University (No. 2017BSQD11).