Abstract 31: Esomeprazole Improves Blood Pressure, Intrauterine Growth, Inflammation, And Vascular Function During Placental Ischemia Through Inhibition Of NLRP3

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Denise C Cornelius ◽  
Xi Wang ◽  
Olivia K Travis ◽  
Corbin A Shields ◽  
G A Tardo ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Resistance Index ◽  
Fetal Weight ◽  
Hypertensive Disorder ◽  
Sprague Dawley ◽  
T Helper 17 ◽  
Intrauterine Growth ◽  
Uterine Perfusion ◽  
Placental Ischemia

Preeclampsia (PE), a multisystem hypertensive disorder of pregnancy is characterized by intrauterine growth restriction (IUGR), inflammation, and vascular dysfunction. NLRP3 inflammasome is a cytoplasmic complex that mediates inflammation and is implicated in CVD. Clinical studies show an association between PE and increased placental NLRP3 expression. We hypothesized that inhibition of NLRP3 using (1) a specific NLRP3 small molecule inhibitor, MCC950 (M9, 20 mg/kg/d, i.p.) or (2) esomeprazole (ESO, 3.5 mg/kg/d, oral), a therapeutic that is safe in pregnancy, would improve MAP, inflammation, IUGR, and vascular dysfunction in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia. Sham (S) or RUPP surgery was performed in pregnant Sprague Dawley rats on gestation day (GD) 14. A subset of rats from both groups received either vehicle, M9, or ESO on GD14-19 (n=9/group). On GD18, Uterine Artery Resistance Index (UARI) was measured via Doppler Ultrasound. MAP, fetal, and placental weight were measured, and blood and tissues were processed for additional analyses on GD19. MAP (mmHg) was elevated in RUPP (133±1) vs S (108±2; p<0.05). Treatment with M9 or ESO in RUPP decreased MAP (111±1 and 115±3, respectively; p<0.05 vs RUPP). Fetal weight (g) was reduced in RUPP (2.1±0.04) vs S (2.4±0.05), and ESO normalized fetal weight (2.4±0.01; p<0.05 vs RUPP). Placental NLRP3 mRNA expression increased 5-fold in RUPP vs S (p<0.05); and was less than 2 fold in M9 and ESO treated RUPP rats (p<0.05 vs RUPP). Inflammatory T-helper 17 and cytolytic NK cells, evaluated by flow cytometry, were increased in the circulation, placenta, and kidney of RUPP vs S controls. Treatment with M9 or ESO normalized both cell populations in all tissues (p<0.05 vs RUPP). UARI was increased in RUPP (0.71±0.03) versus S (0.56±0.01; p<0.05) and was decreased to 0.48±0.01 in M9 and 0.61±0.03 in ESO-treated RUPPs (p<0.05 vs RUPP). Renal vascular resistance (mmHg/mL/min/g) was increased in RUPP (42±8) vs S (23±4, p<0.05) and was normalized to 26±3 after treatment with M9 (p<0.05 vs RUPP). These data implicate NLRP3 in mediating inflammation and vascular dysfunction to cause maternal HTN and IUGR in RUPP; and identify NLRP3 as a potential target and ESO as a potential therapeutic for PE.

scholarly journals Serelaxin improves the pathophysiology of placental ischemia in the reduced uterine perfusion pressure rat model of preeclampsia

2016 ◽  
Vol 311 (6) ◽  
pp. R1158-R1163 ◽  
Author(s):  
Jose A. Santiago-Font ◽  
Lorena M. Amaral ◽  
Jessica Faulkner ◽  
Tarek Ibrahim ◽  
Venkata Ramana Vaka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Rat Model ◽  
Perfusion Pressure ◽  
Resistance Index ◽  
Hypertensive Disorder ◽  
Pregnant Rats ◽  
Tnf Α ◽  
Uterine Perfusion ◽  
Placental Ischemia ◽  
Nitric Oxide Bioavailability

Preeclampsia is a hypertensive disorder of pregnancy that has limited therapeutic options. In healthy pregnancy, relaxin plays an important vasodilatory role to maintain vascular compliance; however, currently, there is no preclinical evidence to support the use of relaxin during preeclampsia. Therefore, the goal of this study was to test the hypothesis that recombinant human relaxin-2 (Serelaxin, Novartis; RLX) could reduce mean arterial pressure (MAP) and improve uterine artery resistance index (UARI) and nitric oxide bioavailability, and/or decrease prepro-endothelin-1 (PPET-1), soluble fms-like tyrosine kinase-1 (sFlt-1), and TNF-α) in the reduced uterine perfusion pressure (RUPP) model of preeclampsia. On day 14 of gestation (GD14), pregnant rats were assigned to normal pregnant (NP), RUPP, RUPP+RLX, or NP+RLX groups. Treated rats received RLX at 0.4 μg/h or RLX2 4 μg/h RLX via minipump implanted on GD14. On GD18, carotid arterial catheters were inserted, and on GD19, MAP and tissues were collected. MAP was increased in RUPP rats compared with NP but was lowered with either dose of RLX. UARI and sFlt-1 were significantly improved in both treated RUPP groups. Total circulating nitrate-nitrite improved and placental PPET-1 and TNF-α were significantly decreased with the higher dose of RLX. Renal cortex PPET-1 was reduced with both doses of RLX. In conclusion, Serelaxin improved blood pressure, sFlt-1, TNF-α, UARI, and nitric oxide bioavailability and PPET-1 in a rat model of preeclampsia, thereby suggesting a potential therapeutic role for RLX in maintaining maternal health and prolonging pregnancy in the face of placental ischemia.

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.

Interferon Gamma Neutralization Reduces Blood Pressure, Uterine Artery Resistance Index, and Placental Oxidative Stress in Placental Ischemic Rats

2021 ◽  
Author(s):  
Olivia K Travis ◽  
Geilda A Tardo ◽  
Chelsea Giachelli ◽  
Shani Siddiq ◽  
Henry T Nguyen ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Vascular Function ◽  
Uterine Artery ◽  
Resistance Index ◽  
Pregnant Rats ◽  
Maternal Hypertension ◽  
Uterine Perfusion ◽  
Placental Ischemia ◽  
Precise Role

Preeclampsia (PE) is characterized by maternal hypertension, intrauterine growth restriction, increased cytolytic natural killer cells (cNKs), which secrete interferon gamma (IFNγ). However, the precise role of IFNγ in contributing to PE pathophysiology remains unclear. Using the Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia, we tested the hypothesis that neutralization of IFNγ in RUPPs will decrease placental reactive oxygen species (ROS) and improve vascular function resulting in decreased MAP and improved fetal growth. On Gestation Day (GD) 14, the RUPP procedure was performed and on GDs 15 and 18, a subset of normal pregnant rats (NP) and RUPP rats were injected with 10μg/kg of an anti rat-IFNγ monoclonal antibody. On GD18, Uterine Artery Resistance Index (UARI) was measured via Doppler Ultrasound and on GD19, mean arterial pressure (MAP) was measured, animals were sacrificed, and blood and tissues were collected for analysis. Increased MAP was observed in RUPP rats compared to NP and was reduced in RUPP+anti-IFNγ. Placental ROS was also increased in RUPP rats compared to NP and was normalized in RUPP+anti-IFNγ. Fetal and placental weights were reduced in RUPP rats, but were not improved following anti-IFNγ treatment. However, UARI was elevated in RUPP compared to NP and was reduced in RUPP+anti-IFNγ. In conclusion, we observed that IFNγ neutralization reduced MAP, UARI, and placental ROS in RUPP recipients. These data suggest that IFNγ is a potential mechanism by which cNKs in contribute to PE pathophysiology and may represent a therapeutic target to improve maternal outcomes in PE.

Impact of hyperleptinemia during placental ischemia-induced hypertension in pregnant rats

2021 ◽  
Author(s):  
Ana C. Palei ◽  
Hunter L. Martin ◽  
Barbara A. Wilson ◽  
Christopher D. Anderson ◽  
Joey P. Granger ◽  
...  
Keyword(s):  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
No Donor ◽  
Induced Hypertension ◽  
Cgmp Signaling ◽  
Uterine Perfusion ◽  
Plasma Leptin ◽  
Placental Ischemia

The prevalence of preeclampsia and obesity have increased. While obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass. Infusion of this adipokine elicits hypertension in non-pregnant rats, but less is known about how hyperleptinemia impacts blood pressure during placental ischemia, an initiating event in the pathophysiology of hypertension in preeclampsia. We tested the hypothesis that hyperleptinemia during reduced uterine perfusion pressure (RUPP) exaggerates placental ischemia-induced hypertension. On gestational day (GD) 14, Sprague-Dawley rats were implanted with osmotic mini-pumps delivering recombinant rat leptin (1 mg/kg per min, i.v.) or vehicle concurrently with the RUPP procedure to induce placental ischemia or Sham. On GD 19, plasma leptin was elevated in Sham+Leptin and RUPP+Leptin. Leptin infusion did not significantly impact mean arterial pressure (MAP) in Sham. MAP was increased in RUPP+Vehicle vs. Sham+Vehicle. In contrast to our hypothesis, placental ischemia-induced hypertension was attenuated by leptin infusion. To examine potential mechanisms for attenuation of RUPP-induced hypertension during hyperleptinemia, endothelial-dependent vasorelaxation to acetylcholine was similar between Sham and RUPP; however, endothelial-independent vasorelaxation to the nitric oxide (NO)-donor, sodium nitroprusside, was increased in Sham and RUPP. These findings suggest that NO/cyclic guanosine monophosphate (cGMP) signaling was increased in the presence of hyperleptinemia. Plasma cGMP was elevated in Sham and RUPP hyperleptinemic groups compared to vehicle groups but plasma and vascular NO metabolites were reduced. These data suggest that hyperleptinemia during placental ischemia attenuates hypertension by compensatory increases in NO/cGMP signaling.

scholarly journals Placental ischemia-stimulated T-helper 17 cells induce preeclampsia-associated cytolytic natural killer cells during pregnancy

2018 ◽  
Vol 315 (2) ◽  
pp. R336-R343 ◽  
Author(s):  
Corbin A. Shields ◽  
Maggie McCalmon ◽  
Tarek Ibrahim ◽  
Dakota L. White ◽  
Jan M. Williams ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Natural Killer ◽  
Cell Activation ◽  
Fetal Weight ◽  
T Helper ◽  
T Helper 17 ◽  
Placental Ischemia ◽  
In Pregnancy

Previous studies have demonstrated that T-helper 17 (TH17) cells and cytolytic natural killer (cNK) cells are increased in women with preeclampsia. In this study we investigated the role of placental ischemia-stimulated TH17 cells in induction of cNK cells in pregnancy. We further assessed the role of TH17 cell-mediated oxidative stress in facilitation of cNK cell activation in pregnancy by treating rats with the SOD mimetic tempol. CD4+/CD25− cells were isolated from reduced uterine perfusion pressure (RUPP) rats and differentiated into TH17 cells in vitro. On day 12 of gestation ( GD12), 1 × 106 placental ischemia-stimulated TH17 cells were injected into normal pregnant (NP) rats (NP + RUPP TH17 rats), and a subset of rats were treated with tempol (30 mg·kg−1·day−1) from GD12 to GD19 (NP + RUPP TH17 + tempol rats). On GD19, cNK cells, mean arterial pressure, fetal weight, and cNK cell-associated cytokines and proteins were measured. Placental cNK cells were 2.9 ± 1, 14.9 ± 4, and 2.8 ± 1.0% gated in NP, NP + RUPP TH17, and NP + RUPP TH17 + tempol rats, respectively. Mean arterial pressure increased from 96 ± 5 mmHg in NP rats to 118 ± 2 mmHg in NP + RUPP TH17 rats and was 102 ± 3 mmHg in NP + RUPP TH17 + tempol rats. Fetal weight was 2.37 ± 0.04, 1.95 ± 0.14, and 2.3 ± 0.05 g in NP, NP + RUPP TH17, and NP + RUPP TH17 + tempol rats, respectively. Placental IFNγ increased from 1.1 ± 0.6 pg/mg in NP rats to 3.9 ± 0.6 pg/mg in NP + RUPP TH17 rats. Placental perforin increased from 0.18 ± 0.18 pg/mg in NP rats to 2.4 ± 0.6 pg/mg in NP + RUPP TH17 rats. Placental levels of granzymes A and B followed a similar pattern. Treatment with tempol did not lower placental cNK cytokines or proteins. The results of the present study identify TH17 cells as a mediator of aberrant NK cell activation that is associated with preeclampsia.

Abstract P208: Imaging The Longitudinal Reduction In Placental Ischemia In Response To Therapeutic Intervention For Preeclampsia

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Dylan J Lawrence ◽  
Carolyn Bayer
Keyword(s):  
Vascular Remodeling ◽  
Therapeutic Response ◽  
Perfusion Pressure ◽  
Sprague Dawley ◽  
Placental Function ◽  
Sprague Dawley Rats ◽  
Uterine Perfusion ◽  
Placental Ischemia ◽  
Phosphodiesterase 5

Preeclampsia is believed to be induced by abnormal vascular remodeling and the resulting placental ischemia during early development. Sildenafil, a phosphodiesterase-5 inhibitor, reduces the maternal symptoms of preeclampsia by promoting angiogenesis and enhancing NO-mediated vasodilation. However, the effect of sildenafil on in vivo placental function has not been demonstrated. We performed longitudinal spectral photoacoustic (sPA) imaging of placental therapeutic response to sildenafil in the reduced uterine perfusion pressure (RUPP) model of preeclampsia. Sprague Dawley rats were administered sildenafil (S) via drinking water beginning on gestational day (GD) 11. Imaging was performed on GD14, 16, and 18 with the RUPP procedure implemented after the first imaging session. sPA images of oxygenation show that the placental ischemia induced by the RUPP surgery (RUPP, n=8, 48%; NP, n=8, 54%), was effectively eliminated by treatment with sildenafil (RUPP+S, n=8, 53%, p<0.05). In addition to improved placental oxygenation, sildenafil was also found to reduce mean arterial pressure in RUPP animals by GD18 (RUPP, 110 mmHg; RUPP+S, 98 mmHg; p<0.05), consistent with prior reports. Our studies demonstrate that sPA imaging can detect changes in placental oxygenation which could be used to indicate in vivo placental therapeutic response. Figure 1: Placental hypoxia in the RUPP is improved by treatment with sildenafil on GD16. B-mode US images (a, c) of anatomy were used to manually select the placenta (p) and average placental oxygenation was calculated. A custom red-blue oxygenation colormap was then overlaid for visualization (b, d). Scale bars = 3mm.

scholarly journals Altered hippocampal arteriole structure and function in a rat model of preeclampsia: Potential role in impaired seizure-induced hyperemia

2016 ◽  
Vol 37 (8) ◽  
pp. 2857-2869 ◽  
Author(s):  
Abbie C Johnson ◽  
Marilyn J Cipolla
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Capillary Density ◽  
Nitric Oxide Donor ◽  
High Cholesterol Diet ◽  
Sprague Dawley ◽  
Capillary Rarefaction ◽  
And Function

We investigated the effect of experimental preeclampsia on hyperemia during seizure in the hippocampus and vascular function and structure of hippocampal arterioles using Sprague Dawley rats (n = 14/group) that were nonpregnant, pregnant (d20), or had experimental preeclampsia (induced by a high cholesterol diet d7–20). Hyperemia was measured via hydrogen clearance basally and during pentylenetetrazol-induced seizure (40–130 mg/kg i.v.). Reactivity of isolated and pressurized hippocampal arterioles to KCl, nitric oxide synthase inhibition with NG-nitro-L-arginine methyl ester and the nitric oxide donor sodium nitroprusside were investigated. Capillary density was quantified via immunohistochemistry. Cerebral blood flow increased during seizure vs. baseline in pregnant (118 ± 14 vs. 87 ± 9 mL/100 g/min; p < 0.05) and nonpregnant rats (106 ± 9 vs. 82 ± 9 mL/100 g/min; p < 0.05) but was unchanged in preeclamptic rats (79 ± 16 vs. 91 ± 4 mL/100 g/min; p > 0.05), suggesting impaired seizure-induced hyperemia in preeclampsia. Hippocampal arterioles from preeclamptic rats had less basal tone, and dilated less to 15 mM KCl (9 ± 8%) vs. pregnant (61 ± 27%) and nonpregnant rats (20 ± 11%). L-NAME had no effect on hippocampal arterioles in any group, but dilation to sodium nitroprusside was similar. Structurally, hippocampal arterioles from preeclamptic rats underwent inward hypotrophic remodeling and capillary rarefaction. Impaired seizure-induced hyperemia, vascular dysfunction, and limited vasodilatory reserve of hippocampal arterioles could potentiate hippocampal injury in preeclampsia especially during eclampsia.

scholarly journals Residual vascular dysfunction in women with a history of preeclampsia

2018 ◽  
Vol 315 (6) ◽  
pp. R1062-R1071 ◽  
Author(s):  
Anna E. Stanhewicz
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Normal Pregnancy ◽  
The United States ◽  
Hypertensive Disorder ◽  
Vascular Endothelial ◽  
Cvd Risk ◽  
History Of ◽  
Hypertensive Disorder Of Pregnancy ◽  
Underlying Mechanisms

Preeclampsia is a hypertensive disorder of pregnancy characterized by new-onset hypertension, proteinuria, and edema occurring after 20 wk of gestation, with a prevalence of ~7–10% of pregnancies in the United States and ~8 million pregnancies worldwide. Despite the postpartum remission of preeclamptic symptoms, women who have had preeclampsia are two to four times more likely to develop cardiovascular disease (CVD) and are significantly more likely to die of CVD compared with women with a history of normal pregnancy. Although the relation between history of preeclampsia and elevated CVD risk is well documented, the mechanism(s) underlying this association remains unclear. One hypothesis explaining this association is that the initial vascular damage and dysfunction sustained during the preeclamptic pregnancy persist chronically. Indeed, even in the absence of, or in advance of, overt CVD women who have had preeclampsia have compromised vascular endothelial function. Emerging mechanistic studies in these women have provided some insight into the underlying mechanisms of this persistent vascular dysfunction and have begun to identify potential therapeutic targets for the prevention or mitigation of CVD progression in this vulnerable population. This review summarizes the existing literature examining vascular function and dysfunction in women with a history of preeclampsia and highlights future directions for mechanistic investigations and development of novel intervention strategies aimed at halting or slowing the progression of CVD in these women.

Abstract P218: Tumor Necrosis Factor Alpha Improves Placental Perfusion And Attenuates Intrauterine Growth Restriction In A Rodent Model Of Preeclampsia

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Laura E Coats ◽  
Adam Z Rawls ◽  
Kathy L Cockrell ◽  
Gabrielle M Chamoun ◽  
Barbara T Alexander
Keyword(s):  
Fetal Growth ◽  
Fetal Liver ◽  
Fetal Brain ◽  
Resistance Index ◽  
Growth Restriction ◽  
Fetal Weight ◽  
Placental Perfusion ◽  
Intrauterine Growth ◽  
Tnf Α ◽  
Maternal Administration

Preeclampsia ( PE ) is not only detrimental to the mother and her fetus during pregnancy, but it is also associated with increased cardiovascular ( CV ) risk in the mother and her intrauterine growth restricted ( IUGR ) offspring in later life. Currently there are no known treatment options for PE beyond early delivery. Thus, there is a critical need to identify therapeutic treatments for PE. The inflammatory cytokine TNF-α is increased in women with PE. In the clinically relevant Reduced Uterine Perfusion Pressure ( RUPP ) model of PE in the rat, TNF-α is also increased and importantly, etanercept abolishes maternal hypertension. Etanercept is a soluble receptor that binds TNF-alpha to inhibit the inflammatory response. Although not yet prescribed for PE, etanercept is non-contraindicated during pregnancy. Therefore, this study tested the hypothesis that maternal administration of etanercept will mitigate IUGR in the RUPP model of PE and that improvement in fetal growth occurs in association with improved uteroplacental perfusion, placental morphology, and placental nutrient transporter protein expression. Sham or RUPP was performed at gestational day 14 ( G14 ). Dams were administered vehicle or the TNF-α inhibitor (etanercept, 0.4 mg/kg, s.c.) at G18. At G20 uterine artery resistance index ( UARI ) was significantly increased in vehicle RUPP (0.69±0.02 mm/s) vs. vehicle Sham (0.60±0.02mm/s)( p <0.05), indicative of reduced uteroplacental perfusion, but UARI was no longer increased in treated RUPP (0.65±0.03 mm/s)( p <0.05). At G20, fetal weight was significantly reduced in vehicle RUPP (3.52g±0.10) vs. vehicle Sham (3.82 g±0.09)( p <0.05). Yet, fetal weight was significantly increased in treated RUPP (3.82g±0.12) vs. vehicle RUPP ( p <0.05). Fetal brain weight did not differ in Sham or RUPP, regardless of maternal treatment. However, fetal liver weight was significantly increased in treated RUPP (0.29g ±0.02) vs. vehicle RUPP (0.24g±0.01)( p <0.05) suggesting attenuation of asymmetric growth restriction. These findings indicate that maternal administration of a TNF-α inhibitor during PE improves fetal growth in association with improved uteroplacental blood flow. Future studies are warranted to investigate the long-term benefit in IUGR offspring.

Flow-mediated vasodilation is impaired in adult rat offspring exposed to prenatal hypoxia

2011 ◽  
Vol 110 (4) ◽  
pp. 1073-1082 ◽  
Author(s):  
J. S. Morton ◽  
C. F. Rueda-Clausen ◽  
S. T. Davidge
Keyword(s):  
Cardiovascular Diseases ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Female Offspring ◽  
Mesenteric Arteries ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Adult Rat ◽  
Increased Risk ◽  
The Impact

There is now a demonstrated association between low birth weight and increased mortality later in life. Changes in fetal development may program the cardiovascular system and lead to an increased risk of cardiovascular diseases later in life. In addition, aging is a risk factor for vascular endothelial-dependent dysfunction. However, the impact of being born intrauterine growth restricted (IUGR) on the normal aging mechanisms of vascular dysfunction is not clear. We hypothesized that IUGR would cause changes in vascular function that would affect the mechanisms of flow-induced vasodilation later in life in an age- or sex-dependent manner. To create an IUGR model, pregnant Sprague-Dawley rats were placed in a hypoxic (11.5% O2) or control (room air, 21% O2) environment from days 15 to 21 of pregnancy. Both male and female offspring were investigated at 4 or 12 mo of age. Vascular function was assessed in small mesenteric arteries using flow-induced vasodilation, a physiological stimuli of vasodilation, in a pressure myograph. Flow-induced vasodilation was unaffected at a young age, but was significantly reduced in aging IUGR compared with aging controls ( P < 0.05). Underlying vasodilator mechanisms were altered such that nitric oxide-mediated vasodilation was abolished in both young adult and aging IUGR males and females and in aging control females ( P > 0.05). Endothelium-derived hyperpolarizing factor-mediated vasodilation was maintained in all groups ( P < 0.01). A change in the mechanisms of vasodilation occurring at an earlier age in IUGR offspring may predispose them to develop cardiovascular diseases as an aging adult.

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