Serelaxin Improves Blood Pressure and Uterine Artery Resistance in the Reduced Uterine Perfusion Pressure (RUPP) Rat Model of Preeclampsia

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.

Download Full-text

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

Download Full-text

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.

Download Full-text

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.

Download Full-text

Increasing Maternal Blood Pressure with Ephedrine Increases Uterine Artery Blood Flow Velocity during Uterine Contraction

Anesthesiology ◽

10.1097/00000542-200203000-00017 ◽

2002 ◽

Vol 96 (3) ◽

pp. 612-616 ◽

Cited By ~ 18

Author(s):

Laurent Ducros ◽

Philippe Bonnin ◽

Bernard P. Cholley ◽

Eric Vicaut ◽

Moncef Benayed ◽

...

Keyword(s):

Blood Flow ◽

Flow Velocity ◽

Uterine Artery ◽

Uterine Contraction ◽

Perfusion Pressure ◽

Resistance Index ◽

Hemodynamic Parameters ◽

Uterine Blood Flow ◽

Uterine Contractions ◽

Uterine Perfusion

Background During labor, ephedrine is widely used to prevent or to treat maternal arterial hypotension and restore uterine perfusion pressure to avoid intrapartum fetal asphyxia. However, the effects of ephedrine on uterine blood flow have not been studied during uterine contractions. The purpose of the study was to assess the effects of ephedrine on uterine artery velocities and resistance index using the Doppler technique during the active phase of labor. Methods Ten normotensive, healthy parturients with uncomplicated pregnancies at term received intravenous ephedrine during labor to increase mean arterial pressure up to a maximum of 20% above their baseline pressure. Peak systolic and end-diastolic Doppler flow velocities and resistance indices were measured in the uterine artery before and immediately after administration of bolus intravenous ephedrine and after ephedrine washout. Umbilical and fetal middle cerebral arterial resistance indices and fetal heart rate were also calculated. Results After ephedrine administration, mean arterial pressure increased by 17 +/- 4%. End-diastolic flow velocity in the uterine artery at peak amplitude of uterine contraction was restored to 74% of the value observed in the absence of contraction. The systolic velocity was totally restored, and the uterine resistance index was significantly decreased, compared with the values in the absence of contraction. Between uterine contractions, ephedrine induced similar but less marked effects. Fetal hemodynamic parameters were not altered by ephedrine administration. Conclusions Bolus administration of intravenous ephedrine reversed the dramatic decrease in diastolic uteroplacental blood flow velocity and the increase in resistance index during uterine contraction, without altering fetal hemodynamic parameters. This suggests that the increase in uterine perfusion pressure during labor could in part restore uterine blood flow to the placenta during uterine contraction.

Download Full-text

Inhibition of 20‐HETE Synthesis Attenuates Elevations in Blood Pressure and Uterine Artery Resistance Index in the RUPP Rat Model of Preeclampsia

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.810.10 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Jessica Faulkner ◽

Sydney Murphy ◽

Nicole Lee ◽

Janae Moseley ◽

Babbette LaMarca

Keyword(s):

Blood Pressure ◽

Rat Model ◽

Uterine Artery ◽

Resistance Index

Download Full-text

Melanocortin-4 Receptor Deficiency Attenuates Placental Ischemia-Induced Hypertension in Pregnant Rats

Hypertension ◽

10.1161/hypertensionaha.118.12028 ◽

2019 ◽

Vol 73 (1) ◽

pp. 162-170 ◽

Cited By ~ 3

Author(s):

Frank T. Spradley ◽

Ana C. Palei ◽

Christopher D. Anderson ◽

Joey P. Granger

Keyword(s):

Blood Pressure ◽

Nervous System ◽

Perfusion Pressure ◽

Wild Type ◽

Pregnant Rats ◽

Melanocortin 4 Receptor ◽

Induced Hypertension ◽

Sympathetic Nervous ◽

Uterine Perfusion ◽

Placental Ischemia

Preeclampsia is a pregnancy-specific disorder of new-onset hypertension linked to placental ischemia. While obesity is a major risk factor for preeclampsia, not all obese pregnant women develop pregnancy-induced hypertension or preeclampsia. Previously, we reported that placental ischemia-induced hypertension is dependent upon intact signaling of the sympathetic nervous system. Moreover, in various models of obesity, blockade of MC4R (melanocortin-4 receptor) signaling protects against the development of hypertension via suppression of the sympathetic nervous system. Less is known about this pathway during obese pregnancy. Although blockade of MC4R may lead to increased body weight during pregnancy, we tested the hypothesis that placental ischemia-induced hypertension is attenuated in obese MC4R-deficient pregnant rats. On gestational day 14, MC4R wild-type or heterozygous-deficient (MC4R-def) rats were subjected to chronic placental ischemia via the reduced uterine perfusion pressure procedure or Sham surgery then examined on gestational day 19. In Sham MC4R-def versus Sham wild-type pregnant rats, there was increased body weight, fat mass, and circulating leptin levels but they had similar fetus weights. Reduced uterine perfusion pressure reduced fetus weights in both strains. Reduced uterine perfusion pressure increased blood pressure in wild-type rats but this response was significantly attenuated in MC4R-def rats, although blood pressure was elevated in Sham MC4R-def over Sham wild-type. These data indicate that while obese MC4R-def pregnant rats have higher blood pressure during pregnancy, placental ischemia-induced hypertension is attenuated in obese MC4R-def pregnant rats. Thus, obese women with abnormal MC4R signaling may be less susceptible to the development of placental ischemia-induced hypertension.

Download Full-text