Early Administration of 17‐Hydroxyprogesterone Caproate to Reduced Uterine Perfusion Pressure (RUPP) Rat Model of Preeclampsia Improves Inflammation, Uterine artery Vasoconstriction and Blood Pressure During Pregnancy

Preeclampsia (PE) is characterized by new onset hypertension in association with elevated natural killer (NK) cells and inflammatory cytokines which are likely culprits for decreased fetal weight during PE pregnancies. As progesterone increases during normal pregnancy, it stimulates Progesterone Induced Blocking Factor (PIBF). PIBF has been shown to decrease inflammation and cytolytic NK cells, both of whichare increased during PE. We hypothesized that PIBF reduces inflammation as a mechanism to improve hypertension in the preclinical RUPP rat model of PE. PIBF (2.0 µg/mL) was administered intraperitoneally on gestational day 15 to either RUPP or normal pregnant (NP) rats. On day 18 carotid catheters were inserted. Mean arterial blood pressure (MAP) and samples were collected on day 19. MAP in NP rats (n=11) was 100±2 mmHg and 105±3 in NP+PIBF (n=8), 122±1 in RUPP rats (n=10), which improved to 110±2 mmHg in RUPP+PIBF rats (n=11), p<0.05. Pup weight was 2.4±0.1 grams (g) in NP, 2.5±0.1 g in NP+PIBF, 1.9±0.1 g in RUPP and improved to 2.1±0.1gin RUPP+PIBF rats. Circulating and placental cytolytic NK cells, IL-17 and IL-6 were significantly reduced while IL-4 and TH2 cells were significantly increased in RUPP rats after PIBF administration. Importantly, vasoactive pathways preproendothelin-1, nitric oxide and sFlt-1 were normalized in RUPP+PIBF rats compared to RUPP rats, p<0.05. Our findings suggest that PIBF normalized IL-4/TH2 cells which was associated with improved inflammation, fetal growth restriction and blood pressure in the RUPP rat model of PE.

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Abstract 076: Early Administration of 17-hydroxyprogesterone Caproate Improves Fetal Growth Restriction Possibly by Reducing Sflt-1 and Placental Cytolytic Nk Cells in Response to Placental Ischemia During Pregnancy

Hypertension ◽

10.1161/hyp.66.suppl_1.076 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Lorena M Amaral ◽

Jamil Elfarra ◽

Denise C Cornelius ◽

Jessica L Faulkner ◽

Mark W Cunningham ◽

...

Keyword(s):

Nk Cells ◽

Normal Pregnancy ◽

Angiogenic Factor ◽

Premature Births ◽

Early Administration ◽

Hydroxyprogesterone Caproate ◽

Infected Cells ◽

17 Hydroxyprogesterone ◽

Uterine Perfusion ◽

Placental Ischemia

Preeclampsia (PE), new onset hypertension, is characterized by elevated anti-angiogenic factor soluble fms-like tyrosine kinase (sFlt-1), cytolytic natural killer (NK) cells and placental ischemia predicted with increased uterine artery resistance (UARI) which are likely culprits for decreased fetal weight during PE pregnancies. Cytolytic NK are an important arm of the immune system killing tumor and infected cells by perforin-granzyme-mediated cytolysis and have been shown to be increased in PE women compared to those with normal pregnancy. Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of spontaneous preterm labor, but is not included in the current management for PE. This study was designed to test the hypothesis that early administration of 17-OHPC could improve pregnancy outcomes in response to placental ischemia. To do so, 17-OHPC (3.32mg/kg) was administered intraperitoneally on gestation day 15 to reduced uterine perfusion pressure (RUPP) rats, UARI was measured using Doppler ultrasound and carotid catheters were inserted on day 18. Blood pressure (MAP), sFlt-1, and placental cytolytic NK cells were measured on GD 19. MAP in normal pregnant (NP) rats (n=12) was 94 ± 2, 126 ± 2 in RUPP (n=27) and 111±1 mmHg in RUPP+17-OHPC (n=15), p <0.05. Pup weight was 2.3±0.09 in NP, 1.9± 0.04 in RUPP rats, which improved to 2.1±0.06 grams in RUPP+17-OHPC p <0.05. UARI was 0.6±0.01 in NP (n=3), 0.8±0.03 in RUPP rats (n=4), which improved to 0.6±0.04 in RUPP+17-OHPC (n=5), p<0.05. Total number of placental NK cells was 8.6 ± 3.1 in NP, 20.2 ±2.4 in RUPP rats, which decreased to 1.6 ± 0.54 % in RUPP+17-OHPC, p<0.05. Activated placental NK cells was 3.8 ± 2.2 in NP, 11.9±2.01 in RUPP , which improved to 0.4 ± 0.2 % in RUPP+17-OHPC, p <0.05. Plasma sFlt-1 was 36.1±7.5, 385.9±141 in RUPP rats (n=5), which was blunted to 110.2±11.1 pg/mL in RUPP+17-OHPC, p<0.05. In conclusion, early administration of 17-OHPC improves sFtl-1, UARI, activated cytolytic NK cells, pup weight and hypertension in response to placental ischemia. Therefore, 17-OHPC should be further considered for addition to the management of PE.

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Reduced uterine perfusion pressure does not influence the endocannabinoid system (ECBS) transcripts in the rat model

Placenta ◽

10.1016/j.placenta.2013.06.083 ◽

2013 ◽

Vol 34 (9) ◽

pp. A27

Author(s):

Mauro Schenone ◽

Zorica Janjetovic ◽

Ramona Phinehas ◽

Brian Brocato ◽

Giancarlo Mari ◽

...

Keyword(s):

Rat Model ◽

Perfusion Pressure ◽

Endocannabinoid System ◽

Uterine Perfusion

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Low Dose of IL-2 Normalizes Hypertension and Mitochondrial Function in the RUPP Rat Model of Placental Ischemia

Cells ◽

10.3390/cells10102797 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2797

Author(s):

Evangeline Deer ◽

Lorena M. Amaral ◽

Nathan Campbell ◽

Sarah Fitzgerald ◽

Owen Herrock ◽

...

Keyword(s):

Inflammatory Response ◽

Rat Model ◽

Low Dose ◽

Perfusion Pressure ◽

Chronic Inflammatory Response ◽

Respiration Rates ◽

Inflammatory Conditions ◽

Uterine Perfusion ◽

Placental Ischemia ◽

New Onset

IL-2 is a cytokine released from CD4+T cells with dual actions and can either potentiate the inflammatory response or quell a chronic inflammatory response depending on its circulating concentration. IL-2 is elevated in many chronic inflammatory conditions and is increased during preeclampsia (PE). PE is characterized by new-onset hypertension during pregnancy and organ dysfunction and increasing evidence indicates that proinflammatory cytokines cause hypertension and mitochondrial (mt) dysfunction during pregnancy. The reduced uterine perfusion pressure (RUPP) model of placental ischemia is a rat model of PE that we commonly use in our laboratory and we have previously shown that low doses of recombinant IL-2 can decrease blood pressure in RUPP rats. The objective of this study was to determine the effects of a low dose of recombinant IL-2 on multi-organ mt dysfunction in the RUPP rat model of PE. We tested our hypothesis by infusing recombinant IL-2 (0.05 ng/mL) into RUPP rats on GD14 and examined mean arterial pressure (MAP), renal, placental and endothelial cell mt function compared to control RUPP. MAP was elevated in RUPP rats (n = 6) compared to controls (n = 5) (122 ± 5 vs. 102 ± 3 mmHg, p < 0.05), but was reduced by administration of LD recombinant IL-2 (107 ± 1 vs. 122 ± 5 mmHg, n = 9, p < 0.05). Renal, placental and endothelial mt ROS were significantly increased in RUPP rats compared to RUPP+ IL-2 and controls. Placental and renal respiration rates were reduced in RUPP rats compared to control rats but were normalized with IL-2 administration to RUPPs. These data indicate that low-dose IL-2 normalized multi-organ mt function and hypertension in response to placental ischemia.

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Abstract P320: Proliferationof Endogenous T-regs Improves the Pathophysiology Associated with Placental Ischemia of Pregnancy

Hypertension ◽

10.1161/hyp.68.suppl_1.p320 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Tarek Ibrahim ◽

Lukasz Przybyl ◽

Ashlyn C Harmon ◽

Denise C Connelius ◽

Mark W Cunningham ◽

...

Keyword(s):

Blood Pressure ◽

Inflammatory Cytokines ◽

Perfusion Pressure ◽

Treg Cells ◽

Proinflammatory Response ◽

Regulatory Interactions ◽

Uterine Perfusion ◽

Placental Ischemia ◽

Pro Inflammatory Cytokines ◽

New Onset

Preeclampsia (PE), new onset hypertension during pregnancy, is associated with pro-inflammatory cytokines and decreased regulatory immune mechanisms such as Tregs, IL-10 and IL-4. We believe this decrease in immune regulatory mechanisms leads to an uncontrolled proinflammatory response which contributes to most of the pathophysiology associated with PE. The Reduced Uterine Perfusion Pressure, RUPP, rat model of induced placental ischemia exhibits similar characteristics as women with PE including high blood pressure, elevated pro-inflammatory cytokines and cells and decreased Tregs, IL-4 and IL-10. Therefore, we hypothesized that stimulating Tregs by administration of a superagonist (SA) would increase the Treg profile in the RUPP rats which could reduce pro-inflammatory cytokines and blood pressure. The RUPP procedure was performed at gestation day 14 (GD14); SA was administered intraperitoneally at GD15, GD18 carotid catheters inserted, and GD19 MAP and pup weight, serum and tissues were collected. MAP in NP rats was 98.6 mmHg ± 4.71, 122.2 mmHg ± 1.84 in RUPPs which was improved to 110.789mmHg ± 1.23 in RUPP+SA. Circulating FoxP3+ Treg cells were 5.987% ± 1.69% of total T-cells population in NP, 0.77% ± 0.49% in RUPP rats but increased to 11.218% ± 2.9% in RUPP+SA; Circulating IL-6 levels were 41.008 ± 4.79 pg/mL in NP, 108.26 ± 25.99 pg/mL in RUPP, and 40.37 ± 4.49 pg/mL in RUPP+SA, Administration of the SA to the NP rats did not affect IL-6 Levels in comparison to NP at 36.79 ± 3.9 pg/mL. Plasma IL-10 Levels were at 58.399 ± 9.527 pg/mL in NP rats, these levels were significantly decreased in the RUPP rats, 26.298 ± 4.33 pg/mL, and treatment of the RUPPs with the SA significantly increased plasma IL-10 levels to 51.5486 ± 3.329 pg/mL. When the SA was given to NP rats, the levels for IL-10 were significantly higher compared to any of the other groups at 85.5207 ± 9.067 pg/mL. Placental Pre-pro Endothelin-1 (PPET-1) was increased 44.42 ± 0.269 fold in RUPP compared to NP 1 ± 0.255, but was decreased to 18.78 ± 0.48 in RUPP+SA. These data suggest an important role for up-regulating Treg cells to enhance the immune regulatory interactions and lower the hypertension without causing further reduction in fetal weight in response to placental ischemia during pregnancy.

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Abstract P174: 17-hydroxyprogesterone Caproate Improves Blood Pressures and Placental Cytolytic Nk Cells in Response to Placental Ischemia During Pregnancy

Hypertension ◽

10.1161/hyp.68.suppl_1.p174 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Lorena M Amaral ◽

Jamil Elfarra ◽

Denise C Cornelius ◽

Mark W Cunningham ◽

Tarek Ibrahim ◽

...

Keyword(s):

Nk Cells ◽

Premature Births ◽

Fetal Demise ◽

Hydroxyprogesterone Caproate ◽

Blood Pressures ◽

17 Hydroxyprogesterone ◽

Uterine Perfusion ◽

Placental Ischemia ◽

Do So ◽

New Onset

Preeclampsia (PE), new onset hypertension, is characterized by decreased fetal weight, elevated cytolytic natural killer (NK) cells and placental ischemia during pregnancy. Cytolytic NK are thought to play a role in fetal demise as they have also been shown to be increased in patients suffering from miscarriage.Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Multiple injections of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of preterm labor, but not for management of PE. We have shown that injections of 17-OHPC to the RUPP rat model of PE improves some but not all facets of PE observed in this model. Therefore this study was designed to test the hypothesis that injections of 17-OHPC on both day 15 (GD15) and GD (18) improve outcomes of hypertension in response to placental ischemia. To do so, 17-OHPC (3.32mg/kg) was administered intraperitoneally on GD 15 and 18 to reduced uterine perfusion pressure (RUPP) rats, carotid catheters were inserted on GD 18 and blood pressure (MAP) andplacental cytolytic NK cells were measured on GD 19. MAP in normal pregnant (NP) rats (n=8) was 104±4,119± 5 in RUPP rats (n=5) and 102±5 mmHgin RUPP+17-OHPC GD15 &18 (n=4), p <0.05.Total number of placental NK cells was 8.5± 3 in NP, 20±2 in RUPP rats, which decreased to 4.7± 3 % in RUPP+17-OHPC GD15 &18, p<0.05. Activated placental NK cells was 3.4± 1.6 in NP, 10.5±2.3 in RUPP, which improved to 2.7± 2.7 % in RUPP+17-OHPCGD15 & 18, p <0.05.In conclusion, administration of 17-OHPC on days 15 and 18 decreased hypertension and NK cells that are associated with PE in the RUPP ratand should be considered for addition to the management of PE.

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