Preeclampsia is associated with hypertension, small-for-gestational-age babies, and increased cytolytic natural killer (NK) cells. The specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. We hypothesized that Reduced Uterine Perfusion Pressure (RUPP) stimulates proliferation and cytolytic activation of NK cells, and that reducing NK cells in RUPP would prevent hypertension, intrauterine growth restriction, and inflammation in response to placental ischemia. RUPP was induced on gestation day (GD) 14 in pregnant rats. NK cells were depleted by i.p. administration of anti-asialo GM1 antibody on GDs 15 and 17. Placental and circulating NK cells were quantified via flow cytometry, mean arterial pressure (MAP), fetal weights, and cytokines were measured on GD 19. Total placental NK cells were 7.4±2% of gated cells in normal pregnant (NP; n=10) and 16.5± 3% of gated cells in RUPP (n=10) rats. Furthermore, cytolytic placental NK cells also increased in RUPP. Depletion of NK cells in RUPP (RUPP + anti-ASGM1) significantly improved MAP and fetal weights. MAP was 108± 2 mmHg in NP, 125± 2 mmHg in RUPP, and 112± 2 mmHg in RUPP + anti-ASGM1 (n=12). Fetal weight was 2.32 ± 0.05 in NP, 1.8± 0.04g in RUPP, and increased to 2.0± 0.04g in RUPP + anti-ASGM1. Placental interferon-γ (IFN-γ) was 40.4± 5.2 pg/mg in NP, 72.17± 3.2 pg/mg in RUPP, and 44.0± 6.5 pg/mg in RUPP + anti-ASGM1 (P<0.05). Placental tumor necrosis factor-α (TNF-α) was 17.9± 1.7 pg/mg in NP, 23.9± 2.2 pg/mg in RUPP, and 12.9± 2.3 pg/mg in RUPP + anti-ASGM1 (P<0.05). Depletion of NK cells significantly lowered MAP, intrauterine growth restriction, and inflammation in RUPP rats indicating that cytolytic NK cells are important in preeclampsia pathophysiology.
Hysterectomy for the control of obstetric hemorrhage is usually associated with significant mortality and morbidity. Prompt intervention to include peripartum hysterectomy may likely decrease the rate of maternal deaths and significant maternal morbidity.
Preeclampsia (PE) is new onset hypertension during pregnancy associated with increased uterine artery resistance (UARI) and an imbalance among CD4+ T lymphocytes and natural killer (NK) cells. We have shown an important role for 17-hydroxyprogesterone caproate (17-OHPC) to improve hypertension and fetal demise in the RUPP rat model of PE. However we have not examined a role for 17-OHPC to improve NK cells and CD4 + TH2 cells as possible mechanisms for improved fetal weight and hypertension. Therefore, we hypothesized that 17-OHPC lowers NK cells while improving the T cell ratio in the RUPP rat. RUPP was surgically induced on gestational day 14 in pregnant rats. 17-OHPC (3.32mg/kg) was administered intraperitoneal on day 15, UARI was measured on day 18. Blood pressure (MAP), blood and tissues were collected on GD 19. MAP in NP rats (n=9) was 100 ± 2, 104±6 in Sham rats (n=8), 128 ± 2 in RUPP (n=11) and 115±3 mmHg in RUPP+17-OHPC (n=10), p <0.05. Pup weight and UARI were improved after 17-OHPC. Total and cytolytic placental NK cells were 38 ±5, and 12 ±2% gate in RUPP rats which decreased to 1.6 ± 0.5 and 0.4 ± 0.2 % gate in RUPP+17OHPC rats. CD4 + T cells were 40±3 in RUPP rats, which significantly decreased to 7±1 RUPP+17-OHPC rats. Circulating and placental TH2 cells were 6.0 ± 1, 0.3±0.1% gate in RUPP rats and 12±1 %, 2±0.5% gate in RUPP+17-OHPC rats, p <0.05 This study identifies new mechanisms whereby 17-OHPC improves outcomes in response to placental ischemia.
Preeclampsia (PE) is characterized by elevated tumor necrosis factor alpha (TNF-α), anti-angiogenic factors such as sFlt-1, increased uterine artery resistance (UARI), and decreased of nitric oxide during pregnancy. Previously we showed that 17-hydroxyprogesterone caproate (17-OHPC) administered into RUPP rats on day 18 of gestation improved hypertension without improving pup weight. We hypothesized that earlier administration of 17-OHPC on day 15 of gestation could improve pathophysiology of PE and fetal outcomes in response to placental ischemia. Carotid catheters were inserted on day 18, mean arterial blood pressure (MAP) and samples were collected on day 19. MAP in normal pregnant (NP) rats was 102± 2, 105±2 in NP+ GD15 17-OHPC, 127 ± 2 in RUPP and 112±1 mmHg in RUPP+GD15 17-OHPC, p<0.05. Pup weight and litter size were improved from 1.9±0.05, 10.1±1.4 in RUPP to 2.1±0.07 grams and 13.2±0.6 in RUPP+ GD15 17-OHPC, p<0.05. UARI was 0.8±0.03 in RUPP which was decreased to 0.6±0.04 in RUPP+ GD15 17-OHPC, p<0.05. Plasma TNF-α levels were 164±34 in RUPP and blunted to 29±9 pg/ml in RUPP+ GD15 17-OHPC, p<0.05. Plasma nitrate-nitrite levels were 10.8±2.3 in RUPP rats and significantly increased to 25.5±5.2 μM in RUPP+GD15 17-OHPC, p<0.05. sFlt-1 levels were 386±141 in RUPP rats, which was reduced to 110.2 ± 11 in RUPP+17-OHPC, p<0.05. These data indicate that GD15 17-OHPC improves pathophysiology in RUPP rats, possibly via improving sFlt-1 reduced NO during pregnancy.
Pregnant rats were dived into normal pregnant (NP) and RUPP groups; RUPP was performed on gestational day (GD) 14, and on GD19 conscious mean arterial blood pressure (MAP) was measured, placentas were collected and mitochondria were isolated. Mitochondrial Electron Transport Chain (ETC) complex I and IV activities were measured spectrophotometrically. Additionally, glutamate/malate was used as complex I substrate to measure respiration. Respiration rates measured included: basal state (no substrates), state 2 (glutamate/malate), state 3 (ADP), state 4 (oligomycin), and maximal state (FCCP). RESULTS: MAP was elevated in RUPP (n¼16) compared to NP rats (n¼14) (119AE2 vs. 100AE2 mmHg, p<0.05). Complex I mediated state 3 and maximal state respiration rates were significantly reduced in RUPP vs. NP (313AE16, n¼7 vs. 423AE15, n¼8, pmol/sec/mg, p<0.01) and (244AE13, n¼7 vs. 300AE11, n¼8, pmol/sec/mg, p<0.01) respectively. Respiratory control ratio (state3/state4) was significantly reduced in RUPP (n¼6) vs. NP rats (n¼8) (7AE1 vs 10AE1, p<0.05). Additionally, ETC complex I (12AE3, n¼3 vs. 23AE2, n¼5 nmol e-/min/mg, P<0.05) and complex IV (509AE14, n¼4 vs. 644AE17, n¼6 nmol e-/min/mg, P<0.01) activities were drastically reduced in RUPP compared to NP rats. CONCLUSION: Impairment of mitochondrial respiration and ETC activities indicate that mitochondrial dysfunction is associated with placental ischemia of pregnancy and thereby could contribute to oxidative stress, hypertension and other pathophysiological features of PE.
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