scholarly journals Investigation of interleukin-2-mediated changes in blood pressure, fetal growth restriction, and innate immune activation in normal pregnant rats and in a preclinical rat model of preeclampsia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mark W. Cunningham ◽  
Lorena M. Amaral ◽  
Nathan E. Campbell ◽  
Denise C. Cornelius ◽  
Tarek Ibrahim ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Nk Cells ◽  
Fetal Growth ◽  
Rat Model ◽  
Fetal Growth Restriction ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Growth Restriction ◽  
High Dose ◽  
Fetal Survival

AbstractTwo important clinical features of preeclampsia (PE) are hypertension and fetal growth restriction. The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE exhibits both of these features. Moreover, RUPP and PE women have elevated vasoconstrictor peptide endothelin-1 (ET-1) and inflammation. Interleukin-2 (IL-2) is a cytokine that regulates NK cell activity and is elevated in miscarriage, PE, and RUPP rats. The objective of this study was to examine a role for IL-2 in NK cell activation, fetal growth restriction, and hypertension during pregnancy by either infusion of IL-2 or blockade of IL-2 (basiliximab) in normal pregnant (NP) and RUPP rats. On gestational day 14, NP and RUPP rats received low (LD), middle (MD), or high dose (HD) IL-2 (0.05, 0.10, or 0.20 ng/ml) IP or basiliximab (0.07 mg per rat) by IV infusion. On day 19, blood pressure (MAP), pup weights, and blood were collected. Basiliximab had no effect on blood pressure, however, significantly lowered NK cells and may have worsened overall fetal survival in RUPP rats. However, IL-2 LD (102 ± 4 mmHg) and IL-2 HD (105 ± 6 mmHg) significantly lowered blood pressure, ET-1, and activated NK cells compared to control RUPPs (124 ± 3 mmHg, p < 0.05). Importantly, IL-2 in RUPP rats significantly reduced fetal weight and survival. These data indicate that although maternal benefits may have occurred with low dose IL-2 infusion, negative effects were seen in the fetus. Moreover, inhibition of IL-2 signaling did not have favorable outcome for the mother or fetus.

scholarly journals The Role of HLAC and NK Cells in Fetal Growth Restriction

2017 ◽  
pp. 142
Author(s):  
Sri Sulistyawati ◽  
Didon M Trimulya ◽  
Supriyadi H Respati ◽  
Soetrisno Soetrisno
Keyword(s):  
Nk Cells ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Nk Cell ◽  
Normal Pregnancy ◽  
Growth Restriction ◽  
Immunohistochemical Method ◽  
Cross Sectional ◽  
The Mean

Objective: To determine the role of HLA-C and NK cell expressions in fetal growth restriction (FGR). Methods: A cross sectional study design was used. This study was conducted at the Obstetrics and Gynecology Department of Dr. Moewardi General Hospital, Surakarta, its affiliated hospitals, and at the Pathological Anatomy Laboratory of the Faculty of Medicine, University of Sebelas Maret Surakarta. A total of 40 samples were included in this study. The samples consisted of 20 normal pregnancies and 20 pregnancies with FGR. HLA-C expression in the trophoblast and NK cells in decidua of the subjects who met the inclusion and exclusion criteria were examined using immunohistochemical method and statistical analysis with T test. Results: The mean expression of HLA-C in the trophoblast in the pregnant group with FGR was 9.021.30, normal pregnancy was 7.96 ± 0.97, p=0.01 (p<0.05). The mean expression of NK cells in decidua of pregnancy with FGR was 10.59 ± 2.11, normal pregnancy was 0.91 ± 8.18, with p=0.00 (p<0.05). Conclusion: The expressions of HLA-C in trophoblast and NK cells in decidua of pregnancy with FGR were higher compared with those of normal pregnancy. [Indones J Obstet Gynecol 2017; 5-3: 142-148] Keywords: fetal growth restriction, HLA-C, NK cells

Inflammation-induced fetal growth restriction and pre-eclampsia are linked to alterations in placental morphometrics in a rat model

Placenta ◽  
2013 ◽  
Vol 34 (9) ◽  
pp. A22-A23
Author(s):  
Tiziana Cotechini ◽  
Shannyn K. Macdonald-Goodfellow ◽  
Charles H. Graham
Keyword(s):  
Fetal Growth ◽  
Rat Model ◽  
Fetal Growth Restriction ◽  
Growth Restriction

Metolazone ameliorates the hypertension and fetal growth restriction in a rat model of preeclampsia

2003 ◽  
Vol 189 (6) ◽  
pp. S90
Author(s):  
Gabriella Pridjian ◽  
Monica Ianosi-Irimie ◽  
Hop Vu ◽  
Candice Pridjian ◽  
Janelle Durst ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Rat Model ◽  
Fetal Growth Restriction ◽  
Growth Restriction

scholarly journals Prenatal Use of Sildenafil in Fetal Growth Restriction and Its Effect on Neonatal Tissue Oxygenation—A Retrospective Analysis of Hemodynamic Data From Participants of the Dutch STRIDER Trial

2020 ◽  
Vol 8 ◽  
Author(s):  
Fieke Terstappen ◽  
Anne E. Richter ◽  
A. Titia Lely ◽  
Freek E. Hoebeek ◽  
Ayten Elvan-Taspinar ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Placebo Group ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Neonatal Intensive Care ◽  
Near Infrared ◽  
Cerebral Oxygenation ◽  
Growth Restriction ◽  
Tissue Oxygen Saturation

Objective: Sildenafil is under investigation as a potential agent to improve uteroplacental perfusion in fetal growth restriction (FGR). However, the STRIDER RCT was halted after interim analysis due to futility and higher rates of persistent pulmonary hypertension and mortality in sildenafil-exposed neonates. This hypothesis-generating study within the Dutch STRIDER trial sought to understand what happened to these neonates by studying their regional tissue oxygen saturation (rSO2) within the first 72 h after birth.Methods: Pregnant women with FGR received 25 mg placebo or sildenafil thrice daily within the Dutch STRIDER trial. We retrospectively analyzed the cerebral and renal rSO2 monitored with near-infrared spectroscopy (NIRS) in a subset of neonates admitted to two participating neonatal intensive care units, in which NIRS is part of standard care. Secondarily, blood pressure and heart rate were analyzed to aid interpretation. Differences in oxygenation levels and interaction with time (slope) between placebo- and sildenafil-exposed groups were tested using mixed effects analyses with multiple comparisons tests.Results: Cerebral rSO2 levels were not different between treatment groups (79 vs. 77%; both n = 14) with comparable slopes. Sildenafil-exposed infants (n = 5) showed lower renal rSO2 than placebo-exposed infants (n = 6) during several time intervals on day one and two. At 69–72 h, however, the sildenafil group showed higher renal rSO2 than the placebo group. Initially, diastolic blood pressure was higher and heart rate lower in the sildenafil than the placebo group, which changed during day two.Conclusions: Although limited by sample size, our data suggest that prenatal sildenafil alters renal but not cerebral oxygenation in FGR neonates during the first 72 post-natal hours. The observed changes in renal oxygenation could reflect a vasoconstrictive rebound from sildenafil. Similar changes observed in accompanying vital parameters support this hypothesis.

scholarly journals Placental trophoblast syncytialization potentiates macropinocytosis via mTOR signaling to adapt to reduced amino acid supply

2021 ◽  
Vol 118 (3) ◽  
pp. e2017092118
Author(s):  
Xuan Shao ◽  
Guangming Cao ◽  
Dunjin Chen ◽  
Juan Liu ◽  
Bolan Yu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Mammalian Target Of Rapamycin ◽  
Nutrient Status ◽  
Maternal Blood ◽  
Mtor Signaling ◽  
Growth Restriction ◽  
Mtor Inhibition ◽  
Fetal Survival

During pregnancy, the appropriate allocation of nutrients between the mother and the fetus is dominated by maternal–fetal interactions, which is primarily governed by the placenta. The syncytiotrophoblast (STB) lining at the outer surface of the placental villi is directly bathed in maternal blood and controls feto–maternal exchange. The STB is the largest multinucleated cell type in the human body, and is formed through syncytialization of the mononucleated cytotrophoblast. However, the physiological advantage of forming such an extensively multinucleated cellular structure remains poorly understood. Here, we discover that the STB uniquely adapts to nutrient stress by inducing the macropinocytosis machinery through repression of mammalian target of rapamycin (mTOR) signaling. In primary human trophoblasts and in trophoblast cell lines, differentiation toward a syncytium triggers macropinocytosis, which is greatly enhanced during amino acid shortage, induced by inhibiting mTOR signaling. Moreover, inhibiting mTOR in pregnant mice markedly stimulates macropinocytosis in the syncytium. Blocking macropinocytosis worsens the phenotypes of fetal growth restriction caused by mTOR-inhibition. Consistently, placentas derived from fetal growth restriction patients display: 1) Repressed mTOR signaling, 2) increased syncytialization, and 3) enhanced macropinocytosis. Together, our findings suggest that the unique ability of STB to undergo macropinocytosis serves as an essential adaptation to the cellular nutrient status, and support fetal survival and growth under nutrient deprivation.

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 03: Ablation Of Endothelial Dysfunction Improves Blood Pressure And Fetal Growth Restriction In A Mouse Model Of Preeclampsia-like Hyperleptinemia

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Jessica L Faulkner ◽  
Derrian Wright ◽  
Simone Kennard ◽  
Galina Antonova ◽  
Iris Z Jaffe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Fold Change ◽  
Growth Restriction ◽  
Mesenteric Arteries ◽  
Pregnant Mice ◽  
Placental Efficiency

Placental ischemia, an initiating event of preeclampsia (PE), increases plasma leptin levels. We recently developed a model of midgestation (gestation day (GD)11-18) leptin infusion mimicking the midgestation rise in leptin levels of PE patients. Our previous work demonstrates that deletion of endothelial mineralocorticoid receptors (ECMR) improves markers of vascular dysfunction in leptin-infused female mice. We hypothesized vascular function improvement with ECMR deletion ablates hypertension and fetal growth restriction in pregnant leptin-infused mice. Pregnant ECMR +/+ (WT) and ECMR -/- (KO) mice were infused with vehicle or leptin by osmotic pump (lep, 0.9mg/kg/day, s.c.) on GD11-18 while implanted with radiotelemeters for conscious blood pressure (BP) measurement and wire myography of thoracic aorta and 2 nd order mesenteric arteries at GD18 (*=P<0.05). Leptin infusion did not decrease maternal weight in any groups. Leptin decreased pup weight (0.86±0.04g WT vs 0.52±0.11 WT+lep*) and placental efficiency (pup/placenta ratio) (9.7±0.7 WT vs 7.9±0.6 WT+lep*) in WT pregnant mice. ECMR deletion prevented leptin-mediated decreases in pup weight (0.91±0.06g KO vs 1.0±0.07 KO+lep) and placental efficiency (9.6±0.5 KO vs 9.4±1.2 KO+lep). Mean arterial pressure (BP) increased in leptin-infused WT (102±3mmHg WT vs 120±12 WT+lep*), but not KO (107±2 KO vs 106±8 KO+lep), mice from GD11-18. Leptin infusion reduced acetylcholine-mediated relaxation in both aorta and mesenteric arteries of WT* and constriction to KCl in mesenteric arteries in WT*, but not KO, pregnant mice (2-way ANOVA, repeated measures). Leptin increased plasma endothelin-1 (ET-1, 1.1±0.3 pg/ml WT vs 4.4±1.8 WT+lep*), placental mRNA expression of prepro-ET-1 (1.9±0.3-fold change from WT*) and ET-1 converting enzyme-1 (1.6±0.3-fold change from WT*) in pregnant WT mice. Leptin infusion also increased adrenal aldosterone-synthase protein (1.4±0.4 WT ratio/β actin vs 3.2±0.3 WT+lep*) and angiotensin II type 1 receptor b (3.5±0.8-fold change from WT*) mRNA in pregnant mice. Collectively, these data indicate that leptin infusion induces hypertension and fetal growth restriction in pregnant mice due to vascular dysfunction and increased ECMR activation in pregnant mice.

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