A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model

Li, Jing; LaMarca, Babbette; Reckelhoff, Jane F.

doi:10.1152/ajpheart.00117.2012

Cited by 173 publications

(158 citation statements)

References 103 publications

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“…Previous work has shown that oxidative stress plays an important role in preeclampsia and RUPP hypertension (25,31), and our present observations suggest that the effects of AICAR may be mediated by a combination of the inhibition of the formation of reactive oxygen species and the stimulation of antioxidant molecules. Similar to our observations with angiogenic balance this effect was only observed in the RUPP groups following AICAR treatment, suggesting a dependence on the presence of placental-ischemia.…”

Section: Discussionsupporting

confidence: 76%

AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat

Banek

Bauer

Needham

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Banek CT, Bauer AJ, Needham KM, Dreyer HC, Gilbert JS. AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat. Am J Physiol Heart Circ Physiol 304: H1159 -H1165, 2013. First published February 15, 2013 doi:10.1152/ajpheart.00903.2012.-Previous studies suggest restoration of angiogenic balance can lower blood pressure and improve vascular endothelium function in models of preeclampsia. Our laboratory has recently reported exercise training mitigates hypertension in an animal model of preeclampsia, but the mechanisms are unknown. AMP-activated protein kinase (AMPK) is stimulated during exercise and has been shown to increase expression of VEGF. Therefore, the purpose of this study was to determine whether AICAR (5-aminoimidazole-4-carboxamide-3-ribonucleoside), a potent AMPK stimulator, would increase circulating VEGF, improve angiogenic potential, decrease oxidative stress, and abrogate placental ischemia-induced hypertension. In rats, reduced uteroplacental perfusion pressure (RUPP) was induced on day 14 of gestation by introducing silver clips on the inferior abdominal aorta and ovarian arteries. AICAR was administered intraperitoneally (50 mg/kg b.i.d.) days 14 -18, and blood pressure and tissues were collected on day 19. RUPP-induced hypertension was ameliorated (P Ͻ 0.05) with AICAR versus RUPP. AICAR increased (P Ͻ 0.05) plasma VEGF and decreased (P Ͻ 0.05) plasma soluble VEGF receptor-1 in the RUPP ϩ AICAR versus RUPP. Antioxidant capacity was restored (P Ͻ 0.05) by AICAR in RUPP placenta. Renal and placental catalase activity was decreased (P Ͻ 0.05) in RUPP ϩ AICAR versus RUPP. Angiogenic potential was increased (P Ͻ 0.05) in RUPP ϩ AICAR versus RUPP. Fetal and placental weights were unaffected by AICAR. Placental AMPK phosphorylation was increased (P Ͻ 0.05) in RUPP ϩ AICAR versus normal pregnant and RUPP. These findings suggest AICAR may be useful to mitigate angiogenic imbalance, renal, and placental oxidative stress and increase in blood pressure associated with RUPP hypertension. Furthermore, placental AMPK phosphorylation was observed only in the setting of ischemia. preeclampsia; hypertension; angiogenic balance; 5-aminoimidazole-4-carboxamide-3-ribonucleoside PREECLAMPSIA, A pregnancy-specific syndrome, is the leading cause of fetal and maternal morbidity and mortality across the world, and unfortunately the incidence has been increasing in recent decades (32, 35). Currently, there are limited treatments available, and early delivery is often indicated to prevent further progression of the syndrome. Consequently, preeclampsia is the leading cause of premature delivery, which is well known to have numerous deleterious effects on neonatal and life-long health (32,35).Recent clinical and experimental studies suggest dysregulation of circulating angiogenic factors results in an angiogenic imbalance that is most notably characterized by an altered ratio of pro-angiogenic (e.g., VEGF) and anti-angiogenic factors (e.g., soluble VEGF receptor-1, or s...

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Section: Discussionsupporting

confidence: 76%

AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat

Banek

Bauer

Needham

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Placental oxidative stress has been shown to be increased in preeclamptic women, and placental and renal oxidative stress is observed in preclinical models preeclampsia, and it is implicated in contributing to the development of vascular dysfunction, proteinuria, and hypertension during pregnancy (9,13,27,28). Importantly reactive oxygen species (ROS) is a byproduct of inflammation and is elevated in response to RUPP CD4ϩ T cells and IL-17-and AT 1 -AA-induced hypertension during pregnancy.…”

Section: Np T Reg Cell Supplementation Normalizes Tgf-␤ In Rupp Ratsmentioning

confidence: 99%

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

Cornelius

Amaral

Harmon

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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The reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits much of the pathology characterizing this disease, such as hypertension, inflammation, suppressed regulatory T cells (T Regs), reactive oxygen species (ROS), and autoantibodies to the ANG II type I receptor (AT1-AA) during pregnancy. The objective of this study was to determine whether supplementation of normal pregnant (NP) TRegs into RUPP rats would attenuate the pathophysiology associated with preeclampsia during pregnancy. CD4 ϩ /CD25ϩ T cells were isolated from spleens of NP and RUPP rats, cultured, and injected into gestation day (GD) 12 normal pregnant rats that underwent the RUPP procedure on GD 14. On GD 1, mean arterial pressure (MAP) was recorded, and blood and tissues were collected for analysis. One-way ANOVA was used for statistical analysis. MAP increased from 99 Ϯ 2 mmHg in NP (n ϭ 12) to 127 Ϯ 2 mmHg in RUPP (n ϭ 21) but decreased to 118 Ϯ 2 mmHg in RUPPϩNP TRegs (n ϭ 17). Circulating IL-6 and IL-10 were not significantly changed, while circulating TNF-␣ and IL-17 were significantly decreased after supplementation of TRegs. Placental and renal ROS were 339 Ϯ 58.7 and 603 Ϯ 88.1 RLU·min Ϫ1 ·mgϪ1 in RUPP and significantly decreased to 178 Ϯ 27.8 and 171 Ϯ 55.6 RLU·min Ϫ1 ·mg Ϫ1 , respectively, in RUPPϩNP TRegs; AT1-AA was 17.81 Ϯ 1.1 beats per minute (bpm) in RUPP but was attenuated to 0.50 Ϯ 0.3 bpm with NP TRegs. This study demonstrates that NP TRegs can significantly improve inflammatory mediators, such as IL-17, TNF-␣, and AT 1-AA, which have been shown to increase blood pressure during pregnancy.hypertension; pregnancy; inflammation; oxidative stress; regulatory T cells PREECLAMPSIA IS A PREGNANCY-ASSOCIATED disorder that affects 5-8% of pregnancies and is a major cause of maternal, fetal, and neonatal morbidity and mortality (9,29,37). Hallmark characteristics of preeclampsia are new-onset hypertension after 20 wk gestation, proteinuria, chronic immune activation, fetal growth restriction, and maternal endothelial dysfunction. The pathophysiological mechanisms that lead to the development of preeclampsia are poorly understood. It is thought that poor invasion of trophoblasts leads to insufficient spiral artery remodeling, resulting in placental ischemia (4, 10, 31). The hypoxic environment that results from this placental ischemia is suggested to be an important factor in the development of oxidative stress and a shift in the balance of antiangiogenic and proangiogenic factors, which plays a role in endothelial dysfunction of the placenta and maternal vasculature (10). Previous studies from our laboratory in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia demonstrate that the total population of CD4-positive (CD4 ϩ ) T cells isolated from RUPP spleens and transferred to NP rats causes similar pathology to that seen in RUPP rats (46), demonstrating a role for this population in mediating pathophysiology in response to placental ischemia. Recent data from both clinical and animal model stud...

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“…13 Three-month-old female Sprague Dawley rats were used. On day 14 of pregnancy, dams were randomly assigned to receive either a Sham (n=17) or RUPP (n=20) surgical procedure (see Methods in the online-only Data Supplement).…”

Section: Reduced Uteroplacental Perfusion Pressure In the Ratmentioning

confidence: 99%

Matrix Metalloproteinase Enhances Big-Endothelin-1 Constriction in Mesenteric Vessels of Pregnant Rats With Reduced Uterine Blood Flow

et al. 2013

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Abstract-Preeclampsia is a leading cause of maternal and fetal morbidity/mortality; however, the pathophysiological mechanisms are unclear. Vascular endothelial dysfunction in preeclampsia has been partially attributed to changes in endothelin-1 (ET-1). Several enzymes, including matrix metalloproteinases (MMPs; particularly MMP-2), cleave the inactive precursor big ET-1 (bET-1) to active ET-1. Notably, expression levels of MMP-2 have been shown to be on the increase in women who subsequently develop preeclampsia. We hypothesized that the increased MMP-2 expression leads to increased bET-1 conversion, thereby increasing vasoconstriction in preeclampsia. A reduced uteroplacental perfusion pressure (RUPP) model of preeclampsia in the rat was used to assess mesenteric artery vascular function. Responses to bET-1 (3-310 nmol/L) and ET-1 (1-200 nmol/L) were studied in the presence or absence of inhibitors of enzymes known to cleave bET-1. Vascular contractility in response to bET-1 was greater in RUPP than Sham (P<0.001), whereas neither responses to ET-1 nor maximal contractility to high potassium salt solution (123.70 mmol/L) were different. MMP inhibition with GM6001 (30 μmol/L) significantly decreased responses to bET-1 in RUPP (P<0.001) but not Sham-operated rats. Interestingly, combined treatment with GM6001 and L-NG-nitroarginine methyl ester (100 μmol/L) revealed a NO modulation of MMPs that was reduced in RUPP. In summary, we found increased vascular contractility to bET-1 in the RUPP model of preeclampsia that was likely attributable to upstream enzymatic pathways. These data are consistent with a greater contribution of MMP to cleavage of bET-1 to ET-1 ex vivo in RUPP, suggesting that this enzyme may be partially responsible for increased bET-1-induced contractility.

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A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model

Cited by 173 publications

References 103 publications

AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat

AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

Matrix Metalloproteinase Enhances Big-Endothelin-1 Constriction in Mesenteric Vessels of Pregnant Rats With Reduced Uterine Blood Flow

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