scholarly journals Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure

2017 ◽  
Vol 131 (23) ◽  
pp. 2753-2762 ◽  
Author(s):  
Jamil Elfarra ◽  
Lorena M. Amaral ◽  
Maggie McCalmon ◽  
Jeremy D. Scott ◽  
Mark W. Cunningham ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Intrauterine Growth Restriction ◽  
Perfusion Pressure ◽  
Interferon Γ ◽  
Growth Restriction ◽  
Pregnant Rats ◽  
Intrauterine Growth ◽  
Uterine Perfusion ◽  
Factor Α

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.

scholarly journals Oxidative Stress and Neurodevelopmental Outcomes in Rat Offspring with Intrauterine Growth Restriction Induced by Reduced Uterine Perfusion

2021 ◽  
Vol 11 (1) ◽  
pp. 78
Author(s):  
Marcelo E. Rains ◽  
Colin B. Muncie ◽  
Yi Pang ◽  
Lir-Wan Fan ◽  
Lu-Tai Tien ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Oxidative Stress Markers ◽  
Neurodevelopmental Outcomes ◽  
Pregnant Rats ◽  
Intrauterine Growth ◽  
Rat Offspring ◽  
Stress Markers ◽  
Uterine Perfusion

Intrauterine growth restriction (IUGR) is a major cause of morbidity and mortality and is worldwide associated with delayed neurodevelopment. The exact mechanism involved in delayed neurodevelopment associated with IUGR is still unclear. Reduced uterine perfusion (RUP) is among the main causes of placental insufficiency leading to IUGR, which is associated with increases in oxidative stress. This study investigated whether oxidative stress is associated with delayed neurodevelopment in IUGR rat pups. Pregnant rats were exposed to RUP surgery on gestational day 14 to generate IUGR rat offspring. We evaluated offspring’s morphometric at birth, and neurodevelopment on postnatal day 21 (PD21) as well as markers of oxidative stress in plasma and brain. Offspring from dams exposed to RUP showed significant (p < 0.05) lower birth weight compared to controls, indicating IUGR. Motor and cognitive deficits, and levels of oxidative stress markers, were significantly (p < 0.05) elevated in IUGR offspring compared to controls. IUGR offspring showed significant (p < 0.05) negative correlations between brain lipid peroxidation and neurocognitive tests (open field and novel object recognition) in comparison with controls. Our findings suggest that neurodevelopmental delay observed in IUGR rat offspring is associated with increased levels of oxidative stress markers.

Abstract 133: Depletion of Natural Killer Cell Activation in Response to Placental Ischemia Improves Hypertension and Intrauterine Growth Restriction During Pregnancy

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Denise C Cornelius ◽  
Jamil Elfarra ◽  
Lorena M Amaral ◽  
Maggie McCalmon ◽  
Mark W Cunningham ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Nk Cells ◽  
Renal Dysfunction ◽  
Natural Killer ◽  
Intrauterine Growth Restriction ◽  
Cell Activation ◽  
Nk Cell ◽  
Growth Restriction ◽  
Intrauterine Growth ◽  
Placental Ischemia

Women with preeclampsia (PE), newly developed hypertension and renal dysfunction during pregnancy, have small-for-gestational-age babies and demonstrate an increase in the cytolytic natural killer (NK) cell activation. The specific role of cytolytic NK cells in the pathophysiology of PE has not been clearly defined. The reduced uterine perfusion pressure (RUPP) model of placental ischemia (PI) exhibits many of the characteristics of PE including hypertension, renal dysfunction, chronic inflammation and intrauterine growth restriction (IUGR). In this study, we tested the hypothesis that PI results in cytolytic activation of NK cells, and examined a role for a reduction in NK cells in RUPP to attenuate PE-like characteristics in response to PI. In this study NK cells were depleted in RUPP rats by intraperitoneal administration of the Anti-asialo GM1 antibody on gestation days 15 and 17. PBMCs and placental lymphocytes were examined via flow cytometry to quantify cytolytic NK cells and to verify NK cell depletion, blood pressure (MAP) and pup weight were measured. While total placental NK cells numbers did not change in response to PI (NP: 14±4.5%; RUPP: 14.3±3.8%), cytolytic activation of placental NK cells significantly increased in response to PI (NP: 3.4±1.1% vs RUPP 10.0±3.4%; p<0.05). Moreover, depletion of NK cells in RUPP (total NK: RUPP: 14.3±3.8% vs RUPP+NKD: 3.5±0.9%) significantly improved blood pressure and intrauterine growth restriction (IUGR): MAP significantly increased in response to PI from 109.5±2.3 mmHg in NP (n=10) to 125.4±2.7 mmHg (n=9) in RUPP rats (p<0.001). Depletion of NK cells with the cell specific depleting antibody significantly lowered blood pressure to 114.4.±1.9 mmHg in RUPP+NKD rats (n=11, p<0.01). Additionally, NK cell depletion in RUPP significantly reduced IUGR in response to PI (1.85±0.06g in RUPP vs. 2.0±0.4g in RUPP+NKD; p<0.05). Depletion of NK cells in RUPP rats was positively associated with lowering blood pressure and blunting IUGR in response to PI. These results suggest a role for cytolytic NK in contributing to hypertension and IUGR in response to PI, potentially identifying previously unknown mechanisms of PE pathophysiology and new therapeutic targets to improve maternal and fetal outcomes of PE.

Abstract P213: Placental Ischemia-Stimulated Natural Killer Cells Contribute To Hypertension, Vascular Dysfunction, And Intrauterine Growth Restriction In Pregnant Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Olivia K Travis ◽  
Cedar Baik ◽  
Geilda A Tardo ◽  
Lorena M Amaral ◽  
Carmilya Jackson ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Intrauterine Growth Restriction ◽  
Vascular Dysfunction ◽  
Growth Restriction ◽  
Fetal Weight ◽  
Direct Role ◽  
Pregnant Rats ◽  
Intrauterine Growth ◽  
Placental Ischemia

The Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia mimics many characteristics of preeclampsia (PE) such as hypertension (HTN), intrauterine growth restriction (IUGR), and increased cytolytic natural killer cells (cNKs). We have previously shown that natural killer (NK) cell depletion in RUPP rats improves PE pathophysiology and that RUPP NKs have a 5-fold increase in cytotoxicity vs normal pregnant NKs. In this study, we tested the hypotheses that (1) RUPP stimulated NKs play a direct role in causing HTN and IUGR in pregnant rats and (2) normal pregnant control (Sham) NKs attenuate HTN and IUGR in RUPP rats. NKs were isolated from the placentas of Sham and RUPP rats on gestation day (GD) 19. On GD14, vehicle or 5x10 6 RUPP NKs were infused i.v. into a subset of Sham rats, and vehicle or 5x10 6 Sham NKs were infused i.v. into a subset of RUPP rats. On GD18, Uterine Artery Resistance Index (UARI) was measured via Doppler Ultrasound; GD19, cNKs were quantified via flow cytometry and MAP, fetal weight, and blood were acquired. Plasma VEGF and sFlt-1 were measured via ELISA. Placental cNKs (% gated) increased from 3±1% in Sham to 19±5% in RUPP and 21±4% in Sham+RUPP NK (p<0.05 vs Sham), and decreased to 3±1% in RUPP+Sham NK (p<0.05 vs RUPP). Circulating cNKs also followed this trend. MAP increased from 102±1 mmHg in Sham to 130±2 mmHg in RUPP and 121±2 mmHg in Sham+RUPP NK (p<0.05 vs Sham), and was blunted to 113±1 mmHg in RUPP+Sham NK (p<0.05 vs RUPP). Fetal weight decreased from 2.4±0.04 g in Sham to 2.1±0.07 g in RUPP and 2.1±0.03 g in Sham+RUPP NK (p<0.05 vs Sham), and this was normalized to 2.3±0.03 g in RUPP+Sham NK (p<0.05 vs RUPP). UARI increased from 0.56±0.05 in Sham to 0.75±0.06 in RUPP and 0.76±0.05 in Sham+RUPP NK (p<0.05 vs Sham), and decreased to 0.64±0.05 in RUPP+Sham NK (p<0.05 vs RUPP). Circulating sFlt-1 increased from 76±15 pg/mL in Sham to 1391±424 pg/mL in RUPP (p<0.05 vs Sham), 780±256 pg/mL in Sham+RUPP NK, and decreased to 67±8 pg/mL in RUPP+Sham NK (p<0.05 vs RUPP). Furthermore, circulating VEGF decreased in RUPP and Sham+RUPP NK compared to Sham (p<0.05), and increased in RUPP+Sham NK (p<0.05 vs RUPP). These data demonstrate a direct role for cNKs to mediate vascular dysfunction in PE and for normal NKs to promote positive maternal and fetal outcomes.

Abstract 017: Cytolytic Natural Killer Cells Play a Direct Role in Causing Hypertension and Intrauterine Growth Restriction in Pregnant Rats

Hypertension ◽  
2019 ◽  
Vol 74 (Suppl_1) ◽  
Author(s):  
Olivia K Travis ◽  
Cedar H Baik ◽  
Carmilya Jackson ◽  
Chelsea Giachelli ◽  
Jan M Williams ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Direct Role ◽  
Pregnant Rats ◽  
Killer Cells ◽  
Intrauterine Growth

Placental HIF-1α, HIF-2α, membrane and soluble VEGF receptor-1 proteins are not increased in normotensive pregnancies complicated by late-onset intrauterine growth restriction

2007 ◽  
Vol 293 (2) ◽  
pp. R766-R774 ◽  
Author(s):  
Augustine Rajakumar ◽  
Arun Jeyabalan ◽  
Nina Markovic ◽  
Roberta Ness ◽  
Carol Gilmour ◽  
...  
Keyword(s):  
Northern Blot ◽  
Intrauterine Growth Restriction ◽  
Northern Blot Analysis ◽  
Late Onset ◽  
Growth Restriction ◽  
Trophoblast Invasion ◽  
Vegf Receptor ◽  
Placental Perfusion ◽  
Intrauterine Growth ◽  
Factor Α

Inadequate trophoblast invasion and spiral artery remodeling leading to poor placental perfusion are believed to underlie the pregnancy pathologies preeclampsia (PE) and intrauterine growth restriction (IUGR). The main objective of this study was to investigate hypoxia-inducible transcription factor-α (HIF-α) and downstream genes (VEGF receptor-1) Flt-1 and soluble fms-like tyrosine kinase 1 (sFlt-1) proteins in IUGR placentas. Placentas from normal pregnant (NP; n = 18), PE ( n = 18), and IUGR ( n = 10) patients were investigated. Normotensive patients with IUGR delivered babies at ≥ 37 wk of gestation with birth weights of <10% and asymmetrical growth. HIF-1α, -2α, Flt-1, and sFlt-1 protein, and mRNA were assessed by Western and Northern blot analyses, respectively. The results are expressed as ratios of the densitometric values for each pair of pathologic and normal placentas, a ratio of 1.0 indicating no difference. Comparable to our earlier studies, the PE/NP ratios for HIF-1α, -2α, and Flt proteins were significantly increased by 50–100% (all P < 0.01 vs. 1.0). Unexpectedly, the IUGR/NP ratios for HIF-1α and -2α proteins were 1.03 ± 0.07 and 0.96 ± 0.16, respectively, and for Flt and sFlt were 1.14 ± 0.15 and 0.95 ± 0.12, respectively (all P = not significant vs. 1.0). Northern blot analysis revealed comparable levels of HIF-α mRNA in abnormal and normal placentas. In contrast to PE, HIF-α proteins and regulated genes are not increased in placentas from normotensive pregnant women delivering small, asymmetrically grown babies ≥ 37 wk of gestation. The absence of an increase in HIF-α protein is not due to insufficient HIF-α mRNA for protein synthesis. Thus, the placentas from women with PE and late IUGR are fundamentally different at the molecular level.

scholarly journals Importance of polymorphic variants of Tumour Necrosis Factor — α gene in the etiology of Intrauterine Growth Restriction

2018 ◽  
Vol 89 (3) ◽  
pp. 160-168 ◽  
Author(s):  
Agnieszka Kaluba-Skotarczak ◽  
Justyna Magiełda ◽  
Anna Romała ◽  
Grażyna Kurzawińska ◽  
Magdalena Barlik ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Intrauterine Growth Restriction ◽  
Tumour Necrosis ◽  
Growth Restriction ◽  
Tumour Necrosis Factor Α ◽  
Intrauterine Growth ◽  
Polymorphic Variants ◽  
Factor Α ◽  
Necrosis Factor
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