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...
Women with preeclampsia (PE), newly developed hypertension and renal dysfunction during pregnancy, have small-for-gestational-age babies and demonstrate an increase in the inflammatory cytokine IL-17, placental oxidative stress, and cytolytic natural killer (NK) cell activation. The stimulus of the cytolytic NK cell phenotype during PE is currently unknown. Moreover, the specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. The reduced uterine perfusion pressure (RUPP) model of placental ischemia exhibits many of the characteristics of preeclampsia including hypertension, renal dysfunction, chronic inflammation and intrauterine growth restriction (IUGR). In this study, we tested the hypothesis that placental ischemia results in cytolytic activation of NK cells, and examined a role for the increased IL-17, in response to placental ischemia, to activate cytolytic NK cells. In this study, blood pressure (MAP) and pup weight were measured, and PBMCs and placental lymphocytes were examined via flow cytometry for surface makers of cytolytic NK cell activation. MAP significantly increased in response to placental ischemia from 103±4.1 mmHg in NP (n=6) to 129.1±3.1 mmHg (n=8) in RUPP rats (p<0.001). Neutralization of IL-17 with a soluble receptor attenuated the blood pressure response to 106.3±2.3 mmHg in RUPP+IL-17RC rats (n=3). Pup weight is significantly decreased in RUPP rats (2.52±0.18g in NP vs 2.03±0.05g in RUPP (p<0.05)), which increased to 2.54±0.36g in RUPP+IL-17RC. Cytolytic activation of circulating NK cells was not significantly changed among any of the groups (NP: 2.49±1.1%; RUPP: 7.74±3.2%; RUPP+IL-17RC:5.50±2.8%). However, cytolytic activation of placental NK cells increased in response to placental ischemia (NP: 3.4±1.1% vs RUPP 10.0±3.4%), and was completely attenuated after treatment with the soluble IL-17 receptor (RUPP+IL-17RC: 0.33±0.17%). These results suggest a role for placental ischemia and increased IL-17 to stimulate cytolytic NK cells. Furthermore, this study links the IL-17 pathway with cytolytic NK cell activation and IUGR in response to placental ischemia, potentially identifying new therapeutic targets to improve maternal and fetal outcomes of PE.
Autoantibodies to the angiotensin II type I receptor (AT1‐AA) play a role in hypertension associated with preeclampsia (PE). We found that Vitamin D (VD) reduces AT1‐AA and blood pressure (MAP) in a rat model of PE. Here we tested the hypothesis that VD would improve MAP and endothelial dysfunction markers associated with AT1‐AA during PE. We infused AT1‐AA (1:40 in saline) via osmotic minipump on gestational day (GD) 12–19 in pregnant rats. Either VD2 (270 IU/day) or VD3 (15 IU/day) were given on GD14–18 by oral gavage. Uterine artery resistance index (UARI) was measured by Doppler sonography on GD18 and MAP measured on GD19 by indwelling catheter. MAP increased in AT1‐AA (121±4 mmHg) compared to normal pregnant (NP) (101±2) but was decreased in AT1‐AA+VD2 (105±2) and AT1‐AA+VD3 (109±2). UARI increased in AT1‐AA rats to 0.57±0.01 compared to NP (0.41±0.02). VD3 reduced UARI to 0.49±0.03. Placental preproendothelin‐1 (ET‐1) mRNA expression increased in AT1‐AA (18.1±2.9‐fold) from NP and was decreased with VD2 (4.3±1.4) and VD3 (1.3±0.3). Plasma 8‐isoprostanes (ROS) increased in AT1‐AA to 1633±179 pg/ml compared to NP (634±197) but was decreased with VD2 (436±81) and VD3 (752±94). sFlt‐1 increased in AT1‐AA (715±189 pg/ml) compared to NP (94±12) and was reduced with both VD2 (77±16) and VD3 (195±7). We have demonstrated that VD improved ET‐1, ROS and sFlt‐1 in response to AT1‐AA in pregnant rats. We believe reducing these factors led to reduced vascular resistance and MAP responses commonly seen in elevated AT1‐AA, as in the case of PE, thereby supporting a role for VD supplementation as a prevention for PE.Support or Funding InformationProject funded by NIH RO1HD067541 and T32HL105324
offspring from these groups (2 nd generational animals) were then fed control diet from weaning to until 3 months of age after weaning. Offspring weight was measured from 3 weeks to 8 weeks of age to obtain weight gain trajectory. Systolic blood pressure (SBP), glucose tolerance test (GTT) and lipid profile (cholesterol, HDL, LDL and triglycerides) were measured at 3 months of age. RESULTS: WT offspring born from MLS mother had similar postnatal weight gain at 8 weeks of age (MLS, group 1: 8.8 AE 0.7 g) compared with offspring born from HTN and control mother (HTN, group 2: 12.3 AE 2.3 g; control, group 3: 11.3 AE 0.5 g)(p¼0.172). Among the three groups, similar glucose levels were obtained by GTT at each timepoint of the curve. There was no difference in SBP among all the WT male offspring groups (MLS, group 1: 156.9 AE 5.5; HTN, group 2: 134.2 AE 11.9 and control, group 3: 138.9 AE 6.3, p¼0.137). Also no difference was seen in the lipid profile between groups (Table, p¼0.994 for cholesterol; p¼0.984 for HDL; p¼0.980 for LDL; p¼0.998 for TG). CONCLUSION: This is one of the first studies to evaluate the effects of fetal programming on 2nd generation offspring. Abnormal metabolic profiles resulting from genetic and environmental exposures in first generation female during pregnancy do not appear to increase the risk of passage of metabolic or cardiovascular dysfunction to the 2nd generation animals fed a normal diet. 181 Administration of 17-hydroxyprogesterone caproate in mid-gestation improves fetal growth possibly by reducing sFlt-1 and placental cytolytic NK cells in the Reduced Uterine Perfusion Pressure (RUPP) rat model of Preeclampsia
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