Maternal Adaptation in Pregnant Hypertensive Rats: Improvement of Vascular and Inflammatory Variables and Oxidative Damage in the Kidney

Iacono, A; Bianco, Giuseppe; Raso, Giuseppina Mattace; Esposito, Emanuela; Bianca, Roberta d’Emmanuele di Villa; Sorrentino, Raffaella; Cuzzocrea, Salvatore; Calignano, Antonio; Autore, Giuseppina; Meli, Rosaria

doi:10.1038/ajh.2009.68

Cited by 17 publications

(17 citation statements)

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“…There is recent evidence that the increased proinflammatory and oxidative markers (malondialdehyde content and protein nitrosylation) seen in SHRs are greatly ameliorated by pregnancy. 16 Together with changes in the renin-angiotensin system in the kidney, reduction of oxidative markers seems to contribute to the reduction of blood pressure near term in SHRs, as observed in our study. Future studies on oxidative stress in pregnant SHRs should be carried out in other tissues and platelets to support the hypothesis that a decrease in oxidative stress near term may contribute to the maintenance of NO and cGMP bioavailability.…”

Section: Discussionsupporting

confidence: 67%

“…The levels obtained from pregnant hypertensive rats were not significantly different from those obtained from the normotensive groups, which were in agreement with previous findings. 15,16,21 These results might be partially explained by an increased production of NO and prostacyclin from vascular endothelium 20 and a hyporeactivity to vasoconstrictors, 34 which may contribute to vasodilation and consequent reduction in peripheral vascular resistance. Although a specific role for NO in the induction of hemodynamic alterations in pregnancy is somewhat controversial, it is widely accepted that an excess of NO is generated by endothelial cells during normal pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…7 Previous studies by our group have shown that a reduction in intraplatelet NO bioavailability associated with platelet hyperaggregability might be involved in thrombotic events in patients with essential hypertension [8][9][10] because NO inhibits platelet adhesion, 11 aggregation 12 and recruitment, 13 as well as the formation of leukocyte-platelet aggregates. 14 In spontaneously hypertensive rats (SHRs), systolic blood pressure (SBP) is reduced to normal values at the end of pregnancy, 15,16 even though cardiac output and total blood volume are increased. This phenomenon has been associated with decreases in responsiveness to vasoconstrictor agents and systemic blood pressure.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the L-arginine–NO–cGMP pathway in spontaneously hypertensive rat platelets: the effects of pregnancy

et al. 2010

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Nitric oxide (NO) is a short-lived intercellular messenger that provides an efficient vascular regulatory mechanism to support homeostasis and prevent thrombosis. Endothelial dysfunction and reduced NO bioavailability have a central role in hypertension associated with pregnancy. The purpose of this study was to investigate the impact of pregnancy on the L-arginine-NO-cGMP pathway in platelets and its correlation to platelet function and blood pressure in normotensive rats and spontaneously hypertensive rats (SHRs). Platelets were obtained from blood on the 20th day of pregnancy from female SHRs (SHR-P) and normotensive controls (P) or age-matched nonpregnant rats (SHR-NP and NP). Intraplatelet NO synthase (NOS) activity was reduced in P compared to NP, despite unchanged L-arginine influx. The expression levels of endothelial NOS (eNOS) and inducible NOS (iNOS) were diminished during pregnancy in normotensive rats. Paradoxically, cyclic guanosine monophosphate (cGMP) levels were similar between NP and P, as were phosphodiesterase type 5 (PDE5) expression and platelet aggregation induced by adenosine diphosphate. In SHRs, L-arginine influx was reduced in SHR-P compared to SHR-NP. SHR-P exhibited impaired NOS activity and reduced iNOS expression compared with SHR-NP. Soluble guanylyl cyclase and PDE5 expression in platelets were lower in SHR-P than in SHR-NP, whereas no differences were noted between groups with respect to cGMP levels. However, increased levels of cGMP were observed in SHR-P compared to normotensive groups and platelet aggregability remained unaltered. In conclusion, these observations prompted the hypothesis that normal platelet aggregation in pregnant SHRs may be related to a reduction in PDE5 expression and consequently the maintenance of cGMP levels, independently of reduced platelet NO bioavailability.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of the L-arginine–NO–cGMP pathway in spontaneously hypertensive rat platelets: the effects of pregnancy

et al. 2010

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“…Indeed, we observed that the Dahl S rat does exhibit worsening hypertension in late pregnancy, in contrast to both the normotensive SD and the hypertensive SHR. Healthy pregnancy is characterized by a decrease in systemic vascular resistance and blood pressure, likely due to increased nitric oxide-mediated vasodilation (40), and this typical response is observed in both the SD and SHR (4,15,19,37). However, the Dahl S rat exhibits a slight but significant increase in MAP, resulting in a ϳ20 mmHg difference in pressure compared with the expected drop that should occur at late pregnancy.…”

Section: R65mentioning

confidence: 99%

The Dahl salt-sensitive rat is a spontaneous model of superimposed preeclampsia

Gillis¹,

Williams²,

Garrett

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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The Dahl salt-sensitive rat is a spontaneous model of superimposed preeclampsia. Am J Physiol Regul Integr Comp Physiol 309: R62-R70, 2015. First published April 22, 2015 doi:10.1152/ajpregu.00377.2014.-The mechanisms of the pathogenesis of preeclampsia, a leading cause of maternal morbidity and death worldwide, are poorly understood in part due to a lack of spontaneous animal models of the disease. We hypothesized that the Dahl salt-sensitive (S) rat, a genetic model of hypertension and kidney disease, is a spontaneous model of superimposed preeclampsia. The Dahl S was compared with the Sprague-Dawley (SD) rat, a strain with a well-characterized normal pregnancy, and the spontaneously hypertensive rat (SHR), a genetic model of hypertension that does not experience a preeclamptic phenotype despite preexisting hypertension. Mean arterial pressure (MAP, measured via telemetry) was elevated in the Dahl S and SHR before pregnancy, but hypertension was exacerbated during pregnancy only in Dahl S. In contrast, SD and SHR exhibited significant reductions in MAP consistent with normal pregnancy. Dahl S rats exhibited a severe increase in urinary protein excretion, glomerulomegaly, increased placental hypoxia, increased plasma soluble fms-like tyrosine kinase-1 (sFlt-1), and increased placental production of tumor necrosis factor-␣ (TNF-␣). The Dahl S did not exhibit the expected decrease in uterine artery resistance during late pregnancy in contrast to the SD and SHR. Dahl S pups and litter sizes were smaller than in the SD. The Dahl S phenotype is consistent with many of the characteristics observed in human superimposed preeclampsia, and we propose that the Dahl S should be considered further as a spontaneous model to improve our understanding of the pathogenesis of superimposed preeclampsia and to identify and test new therapeutic targets for its treatment.pregnancy; hypertension; proteinuria; uterine artery resistance; animal model; superimposed preeclampsia; TNF-␣; HIF-1␣; sFLT-1 PREECLAMPSIA is characterized by hypertension, proteinuria, and endothelial dysfunction after the twentieth week of pregnancy. Preeclampsia is currently among the leading causes of maternal morbidity and death worldwide, affecting approximately 5% of all pregnancies in the United States (35, 38). Preexisting chronic hypertension or chronic kidney disease dramatically increases the risk of developing superimposed preeclampsia during pregnancy, with an estimated 25% of chronically hypertensive women (39) and 30% of women with chronic kidney disease (23) developing superimposed preeclampsia. Furthermore, women with superimposed preeclampsia have an even greater risk of adverse maternal and fetal outcomes compared with women with de novo preeclampsia (8). Despite the severity and incidence of this disease, the mechanisms of the pathogenesis of preeclampsia remain unclear. There is currently no effective treatment available, and the only known "cure" for preeclampsia is the delivery of the placenta. There is also a potential for consequences o...

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“…Hypertension in the spontaneously hypertensive rat is ameliorated during pregnancy, an effect that is associated with a reduction in the renal AT 1 R:AT 2 R ratio and decreased inflammation as indicated by downregulation of nuclear factor-κB in the kidney. 30 Collectively these findings suggest that the AT 2 R suppresses AT 1 R-mediated immune system activation within the kidney during pregnancy. Because the increase in the renal Th1:Th2 ratio preceded the rise in arterial pressure during late gestation in AT 2 R-KO mice, this suggests that renal inflammation may contribute to pregnancy-induced hypertension.…”

Section: Discussionmentioning

confidence: 79%

Role of Inflammation and the Angiotensin Type 2 Receptor in the Regulation of Arterial Pressure During Pregnancy in Mice

et al. 2014

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Abstract-During normal pregnancy the renin-angiotensin system is activated, yet pregnant women are resistant to the pressor effects of angiotensin II. Our aim was to determine the role of the angiotensin type 2 receptor (AT 2 R) in the regulation of arterial pressure, natriuresis, and immune cell infiltration during pregnancy. Mean arterial pressure was measured via telemetry, and flow cytometry was used to enumerate immune cell infiltration in 14-week-old wild-type and AT 2 R knockout mice during gestation. In wild-type mice, mean arterial pressure decreased during gestation, reaching a nadir at gestational day 9 (-6±2 mm Hg) and returned to near preconception levels during late gestation. In AT 2 Rdeficient mice, the midgestational decrease in mean arterial pressure was absent. Furthermore, mean arterial pressure was significantly increased during late gestation compared with wild-type mice (≈10 mm Hg). As expected, circulating immune cell activation was suppressed during pregnancy. However, this response was absent in AT 2 R-deficient mice. While renal immune cell infiltration was similar between the genotypes, there was a significant T cell phenotypic switch toward a proinflammatory T-helper 1 phenotype in AT 2 R-deficient mice. These data indicate that the AT 2 R plays an important role in arterial pressure regulation and may modulate T cell activation and renal cytokine production during pregnancy. Therefore, deficits in AT 2 R expression may contribute to pregnancy-induced hypertension and thus represents a potential therapeutic target.

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Maternal Adaptation in Pregnant Hypertensive Rats: Improvement of Vascular and Inflammatory Variables and Oxidative Damage in the Kidney

Abstract: The increased proinflammatory and oxidative variables, seen in SHR, are strongly ameliorated by pregnancy. In pregnant SHR animals, the adaptive and compensative changes of RAS and inflammation in the kidney seem to contribute to the reduction of blood pressure near term.

Cited by 17 publications

References 32 publications

Characterization of the L-arginine–NO–cGMP pathway in spontaneously hypertensive rat platelets: the effects of pregnancy

Characterization of the L-arginine–NO–cGMP pathway in spontaneously hypertensive rat platelets: the effects of pregnancy

The Dahl salt-sensitive rat is a spontaneous model of superimposed preeclampsia

Role of Inflammation and the Angiotensin Type 2 Receptor in the Regulation of Arterial Pressure During Pregnancy in Mice

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