Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

Abstract

Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14 -18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 Ϯ 2 mmHg compared with 102 Ϯ 3 mmHg in NP and decreased to 113 Ϯ 3 mmHg with VD2 and 115 Ϯ 3 mmHg with VD3 in RUPP rats. Circulating CD4ϩ T cells increased in RUPP to 7.90 Ϯ 1.36% lymphocytes compared with 2.04 Ϯ 0.67% in NP but was lowered to 0.90 Ϯ 0.19% with VD2 and 4.26 Ϯ 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 Ϯ 0.4 bpm in RUPPs to 8.3 Ϯ 0.5 bpm with VD2 and to 15.4 Ϯ 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 Ϯ 2.1-fold change from NP) and decreased with both VD2 (3.3 Ϯ 1.1-fold) and VD3 (3.1 Ϯ 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 Ϯ 6.6 pg/ml in VD2-treated and 91.0 Ϯ 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 Ϯ 19.9 pg/ml in RUPP rats. VD treatment reduced CD4ϩ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia. hypertension; immune activation; preeclampsia; vitamin D PREECLAMPSIA (PE) IS A CLINICAL condition occurring in up to 7% of pregnancies in the United States commonly manifesting in late gestation (Ͼ20 wk gestation) with hypertension, placental ischemia, and low birth weight (5,27,47,48,58). Current treatment strategies for preeclampsia are targeted at safely lowering blood pressure and alleviating maternal complications (5, 48). PE pregnancies are characterized by an abnormal immune profile compared with that seen in normal pregnancies. PE women exhibit an altered immune balance favoring proinflammatory factors, such as CD4ϩ T cells, B cells, inflammatory cytokines, and autoantibodies to the angiotensin type 1 receptor (AT 1 -AA), which are known to stimulate production of antiangiogenic protein-soluble FMS-like tyrosine kinase-1 (sFlt-1) (18,33,34,56,57). In contrast, anti-inflammatory T regulatory cells (TREGs) are decreased in PE (22,53,56). These immune alterations are recapitulated in the established experimental model of PE, the reduced uterine perfusion pressure (RUPP) rat (1,20,21). Adoptive transfer of CD4ϩ T cells from RUPP rats induces hypertension, AT 1 -AA, inflammatory cytokines and sFlt-1, and endothelin-1 (ET-1) in normal pregnant rats, indicating the significant role these cells play in the pathogenesis of this disease (63). Furthermore, AT 1 -AA and sFlt-1 play a significant role in the development of endothelial dysfunction and hyp...

Vitamin D restores angiogenic balance and decreases tumor necrosis factor‐α in a rat model of pre‐eclampsia

“…Reduced maternal PE and increased sFlt‐1 were found in women with PE compared with normotensive women . Consistent with these previous studies, VitD treatment decreased sFlt‐1 and lowered high blood pressure and uterine perfusion pressure in a rat PE model . In the present study, we also noted increased placental VEGF and decreased sFlt‐1 in the VitD‐treated PE‐induced dams with VitD.…”

“…38 Consistent with these previous studies, VitD treatment decreased sFlt-1 and lowered high blood pressure and uterine perfusion pressure in a rat PE model. 20 In the present study, we also noted increased placental VEGF and decreased sFlt-1 in the VitD-treated PE-induced dams with VitD. This indicates that maternal VitD supplementation is crucial in restoring angiogenic balance.…”

“…Few data are available on the effect of supplementation on angiogenesis and inflammation in relation to PE. VitD treatment can reduce blood pressure in a reduced uterine perfusion pressure rat model of PE, and may improve treatment of hypertension in response to placental ischemia, but the underlying mechanism via which VitD supplementation improves pathophysiology in the rat model of PE remains unclear. The aim of this study was therefore to investigate the effect of VitD on circulating angiogenic markers and inflammatory cytokine levels in a rat model of PE.…”

Efectos de la Aspirina en Fetos de Rata con Reducción de la Presión de la Perfusión Uterina

“…En la literatura no hay cifras descritas al respecto. Sin embargo, Fushima et al menciona en su estudio que la ligadura de los vasos uterinos causa muertes embrionarias significativas, al igual que Faulkner et al (2016). Por otro lado, en este estudio también se observó que los abortos presentes en cada grupo se encontraban en zonas próximas a la ligadura de vasos ováricos o vasos uterinos, lo que refuerza la idea de que las muertes pueden deberse a la intervención quirúrgica.…”

Meta‐analysis of the effect of the maternal vitamin D level on the risk of spontaneous pregnancy loss

“…A data abstraction form was developed to extract data on general information (article title, authors, and year of publication), study method (case-control or cohort study), participants (number, mean age, and loss to follow-up), mean vitamin D level (cutoff level used [10,15,20, and 30 ng/mL]), serum 25(OH)D quantification method (enzyme-linked immunosorbent assay, electrochemiluminescence assay, enzymatic immunoassay, or mass spectrometry), and definitions of SPL. Two authors (ZH and XJ) independently extracted original data from the selected papers using the developed data abstraction form, and a third author (LX) made a decision when disagreements occurred.…”