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Fetal programming effects of pentaerythritol tetranitrate in a rat model of superimposed preeclampsia.

ABSTRACT: Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in DSSR offspring fed with normal chow or high-salt diet. Upon high-fat diet (HFD) feeding, offspring from PETN-treated mother showed improved glucose tolerance despite similar weight gain. Unexpectedly, maternal PETN treatment significantly potentiated the HFD-induced blood pressure elevation in male DSSR offspring. Endothelium-derived hyperpolarization factor (EDHF)-mediated vasodilation was similar between NCD-fed and HFD-fed control offspring but was markedly reduced in HFD-fed PETN offspring. EDHF genes were downregulated in the vasculature of HFD-fed PETN offspring, which was associated with epigenetic changes in histone modifications. In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improves fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure response to HFD by epigenetic modifications of EDHF genes. KEY MESSAGES: The core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads to • Improvement of fetal growth; • No changes of maternal blood pressure or markers of preeclampsia; • Amelioration of HFD-induced glucose intolerance in adult offspring; • No changes in blood pressure development of the offspring on normal chow or high salt-diet; • Potentiation of blood pressure elevation of the offspring on HFD.

SUBMITTER: Man AWC

PROVIDER: S-EPMC7447665 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Fetal programming effects of pentaerythritol tetranitrate in a rat model of superimposed preeclampsia.

Man Andy W C AWC Chen Min M Zhou Yawen Y Wu Zhixiong Z Reifenberg Gisela G Daiber Andreas A Münzel Thomas T Xia Ning N Li Huige H

Journal of molecular medicine (Berlin, Germany) 20200803 9

Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in ...[more]

PMID: 32748067

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Project description:Aims:Current antihypertensive therapies cannot cure hypertension and a life-long medication is necessary. Maternal treatment may represent a promising strategy for hypertension treatment. We have previously shown that maternal treatment of spontaneously hypertensive rats (SHR) with pentaerythritol tetranitrate (PETN) leads to a persistent blood pressure reduction in the female offspring. The underlying mechanisms include improved endothelial function resulting from long-lasting epigenetic changes. In the present study, we address the renal effects of maternal PETN treatment. Methods and Results:F0 parental SHR were fed with either normal chow or PETN-containing (1 g/kg) chow ad libitum from the time point of mating to the end of lactation period. The F1 offspring received normal chow without PETN from the time point of weaning (at the age of 3 weeks). At the age of 16 weeks, female PETN offspring showed lower blood pressure than the control. No difference was observed in male offspring. All following experiments were performed with kidneys from 16-week-old female offspring. Maternal PETN treatment reduced the mRNA and protein expression of angiotensin-converting enzyme (ACE) and basic fibroblast growth factor (FGF2), resulting from epigenetic modifications found at the proximal promoter regions. The expression levels of mineralocorticoid receptor (MR) and factors in the MR signalling pathway (Rac1 and Sgk1) were also reduced by PETN. Major profibrotic cytokines, including Wnt4, TNF-alpha, TGF-beta, and MMP9, were downregulated by PETN, which was associated with reduced collagen deposition and glomerulus sclerosis in the kidney of PETN offspring. In addition, PETN treatment also decreased the markers of inflammation and immune cell infiltration in the kidneys. Conclusions:PETN maternal treatment leads to epigenetic changes in the kidney of female SHR offspring. The reduced renal inflammation, alleviated kidney fibrosis, and decreased MR signalling are potential mechanisms contributing to the observed blood pressure-lowering effect.

Project description:In this paper, ReaxFF force field combined with molecular dynamics method was used to study the ignition, deflagration, and detonation of pentaerythritol tetranitrate (PETN) induced by hot spots. The hot spot is 5.6% of the total volume. When the hot spot temperature is 1000 K, the deflagration and detonation of PETN cannot be observed in the simulation time of 200 ps. When the hot spot temperature is 2000 K, it corresponds to the heating time of 20 to 50 ps, deflation and detonation were observed. During hot spot ignition, the products of decomposition of the condensed phase PETN are dominated by NO2 and HONO. The energy required for the C-C bond and C-ONO2 bond cleavage in PETN is high, resulting in only a small amount of CH2O and NO3 during the reaction. Small nitrogen-containing molecules (such as NO2, NO3, HONO, HNO3, etc.) mainly exist during thermal equilibrium, while the number of N2 increases sharply during the thermal runaway stage, and a small amount of NH3 and NH2 are also produced. H2O molecules are formed before CO2 and N2 are produced, and the number always dominates. During the thermal runaway, the entire system can maintain a spontaneous reaction, resulting in a sharp rise in temperature of about 2500 K in 20 ps. During this phase, the catalytic effect of H2O accelerates the formation of CO2 and N2 due to the near Chapman-Jouguet point in the crystal. PETN is a weak oxygen balance explosive that results in a small amount of CO and H2 production during the thermal instability phase. When the reaction is balanced, the relative molecular mass is close to or exceeds that of PETN. The product is only less than 1% of the total mass fraction, while the small molecule product is as high as 78%, and some relative molecular masses are [75,225]. The intermediates account for about 21%. Rapid and complex reaction events make it difficult to accurately predict the structure of these intermediates by existing experiments and calculations, which will be the focus of future research.

Project description:Animal models that recapitulate human diseases and disorders are widely used to investigate etiology, diagnosis, and treatment of those conditions in people. Disorders during pregnancy are particularly difficult to explore as interventions in pregnant women are not easily performed. Therefore, models that allow for pre-conception investigations are advantageous for elucidating the mechanisms involved in adverse pregnancy outcomes that are responsible for both maternal and fetal morbidity, such as preeclampsia. The Blood Pressure High (BPH)/5 mouse model has been used extensively to study the pathogenesis of preeclampsia. The female BPH/5 mouse is obese with increased adiposity and borderline hypertension, both of which are exacerbated with pregnancy making it a model of superimposed preeclampsia. Thus, the BPH/5 model shares traits with a large majority of women with pre-existing conditions that predisposes them to preeclampsia. We sought to explore the genome of the BPH/5 female mouse and determine the genetic underpinnings that may contribute to preeclampsia-associated phenotypes in this model. Using a whole genome sequencing approach, we are the first to characterize the genetic mutations in BPH/5 female mice that make it unique from the closely related BPH/2 model and the normotensive background strain, C57Bl/6. We found the BPH/5 female mouse to be uniquely different from BPH/2 and C57Bl/6 mice with a genetically complex landscape. The majority of non-synonymous consequences within the coding region of BPH/5 females were missense mutations found most abundant on chromosome X when comparing BPH/5 and BPH/2, and on chromosome 8 when comparing BPH/5 to C57Bl/6. Genetic mutations in BPH/5 females largely belong to immune system-related processes, with overlap between BPH/5 and BPH/2 models. Further studies examining each gene mutation during pregnancy are warranted to determine key contributors to the BPH/5 preeclamptic-like phenotype and to identify genetic similarities to women that develop preeclampsia.

Dataset Information

Fetal programming effects of pentaerythritol tetranitrate in a rat model of superimposed preeclampsia.

Publications

Fetal programming effects of pentaerythritol tetranitrate in a rat model of superimposed preeclampsia.

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