Characterization of Mitochondrial Bioenergetics in Preeclampsia.

Preeclampsia (PE) is characterized by new onset hypertension during pregnancy and is associated with oxidative stress, placental ischemia, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Mitochondrial (mt) dysfunction in PE and various sources of oxidative stress, such as monocytes, neutrophils, and CD4 + T cells, have been identified as important players in the pathophysiology of PE. We have established the significance of AT1-AA, TNF-α, and CD4 + T cells in causing mitochondrial (mt) dysfunction in renal and placental tissues in pregnant rats. Although the role of mt dysfunction from freshly isolated intact placental mitochondria has been compared in human PE and normally pregnant (NP) controls, variations among preterm PE or term PE have not been compared and mechanisms contributing to mt ROS during PE are unclear. Therefore, we hypothesized PE placentas would exhibit impaired placental mt function, which would be worse in preterm PE patients than in those of later gestational ages. Immediately after delivery, PE and NP patient's placentas were collected, mt were isolated and mt respiration and ROS were measured. PE patients at either < or >34 weeks gestational age (GA) exhibited elevated blood pressure and decreased placental mt respiration rates (state 3 and maximal). Patients delivering at >34 weeks exhibited decreased Complex IV activity and expression. Placental mtROS was significantly reduced in both PE groups, compared to NP placental mitochondria. Collectively, the study demonstrates that PE mt dysfunction occurs in the placenta, with mtROS being lower than that seen in NP controls. These data indicate why antioxidants, as a potential target or new therapeutic agent, may not be ideal in treating the oxidative stress associated with PE.

NAMPT single-nucleotide polymorphism rs1319501 and visfatin/NAMPT affect nitric oxide formation, sFlt-1 and antihypertensive therapy response in preeclampsia.

Aim: We examined the relationships between visfatin/NAMPT and nitrite concentrations (a marker of nitric oxide [NO] formation) or sFlt-1 levels in 205 patients with preeclampsia (PE) responsive or nonresponsive to antihypertensive therapy, and whether NAMPT SNPs rs1319501 and rs3801266 affect nitrite concentrations in PE and 206 healthy pregnant women. Patients & methods: Circulating visfatin/NAMPT and sFlt-1 levels were measured by ELISA, and nitrite concentrations by using an ozone-based chemiluminescence assay. Results: In nonresponsive PE patients, visfatin/NAMPT levels were inversely related to nitrite concentrations and positively related to sFlt-1 levels. NAMPT SNP rs1319501 affected nitrite concentrations in nonresponsive PE patients and was tightly linked with NAMPT functional SNPs in Europeans. Conclusion:NAMPT SNP rs1319501 and visfatin/NAMPT affect NO formation, sFlt-1 levels and antihypertensive therapy response in PE.

Vitamin D supplementation reduces some AT1-AA-induced downstream targets implicated in preeclampsia including hypertension.

Autoantibodies to the ANG II type I receptor (AT1-AA) are associated with preeclampsia (PE). We found that vitamin D supplementation reduced AT1-AA and blood pressure (MAP) in the RUPP rat model of PE. However, it was undetermined whether the decrease in AT1-AA was the mechanism whereby vitamin D lowered MAP or if it were through factors downstream of AT1-AA. Uterine artery resistance index, placental ET-1, and soluble FMS-like tyrosine kinase-1 are increased with AT1-AA-induced hypertension and are considered markers of PE in pregnant women. Therefore, we hypothesized that vitamin D would reduce PE factors during AT1-AA-induced hypertension and could lower blood pressure in a model of hypertension during pregnancy without PE features. Either ANG II (50 ng·kg-1·day) or AT1-AA (1:40) was infused from gestational day (GD) 12-19. vitamin D2 (VD2, 270 IU/day) or vitamin D3 (VD3, 15 IU/day) was administered orally from GD14-GD18. MAP (mmHg) increased in AT1-AA (121 ± 4) and ANG II (113 ± 1)-infused pregnant rats compared with normal pregnant rats (NP) (101 ± 2) but was lower in AT1-AA+VD2 (105 ± 2), AT1-AA+VD3 (109 ± 2), ANG II+VD2 (104 ± 4), and ANG II+VD3 (104 ± 3). VD2 and/or VD3 improved PE features associated with AT1-AA during pregnancy, while ANG II did not induce such features, supporting the hypothesis that AT1-AA induces PE features during pregnancy, and these are improved with vitamin D. In this study, we demonstrate that vitamin D improved many factors associated with PE and reduced blood pressure in a hypertensive model without PE features, indicating that vitamin D could be beneficial for various hypertensive disorders of pregnancy.

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia.

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 ± 2 mmHg compared with 102 ± 3 mmHg in NP and decreased to 113 ± 3 mmHg with VD2 and 115 ± 3 mmHg with VD3 in RUPP rats. Circulating CD4+ T cells increased in RUPP to 7.90 ± 1.36% lymphocytes compared with 2.04 ± 0.67% in NP but was lowered to 0.90 ± 0.19% with VD2 and 4.26 ± 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 ± 0.4 bpm in RUPPs to 8.3 ± 0.5 bpm with VD2 and to 15.4 ± 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 ± 2.1-fold change from NP) and decreased with both VD2 (3.3 ± 1.1-fold) and VD3 (3.1 ± 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 ± 6.6 pg/ml in VD2-treated and 91.0 ± 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 ± 19.9 pg/ml in RUPP rats. VD treatment reduced CD4+ 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.