Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms

2011 ◽  
Vol 301 (1) ◽  
pp. H247-H252 ◽  
Author(s):  
Emrush Rexhaj ◽  
Jonathan Bloch ◽  
Pierre-Yves Jayet ◽  
Stefano F. Rimoldi ◽  
Pierre Dessen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fetal Programming ◽  
Vascular Function ◽  
Histone Deacetylase Inhibitors ◽  
Vascular Dysfunction ◽  
Trichostatin A ◽  
Epigenetic Mechanism ◽  
Maternal Undernutrition ◽  
Underlying Mechanisms ◽  
Pulmonary Vascular Dysfunction

Insults during the fetal period predispose the offspring to systemic cardiovascular disease, but little is known about the pulmonary circulation and the underlying mechanisms. Maternal undernutrition during pregnancy may represent a model to investigate underlying mechanisms, because it is associated with systemic vascular dysfunction in the offspring in animals and humans. In rats, restrictive diet during pregnancy (RDP) increases oxidative stress in the placenta. Oxygen species are known to induce epigenetic alterations and may cross the placental barrier. We hypothesized that RDP in mice induces pulmonary vascular dysfunction in the offspring that is related to an epigenetic mechanism. To test this hypothesis, we assessed pulmonary vascular function and lung DNA methylation in offspring of RDP and in control mice at the end of a 2-wk exposure to hypoxia. We found that endothelium-dependent pulmonary artery vasodilation in vitro was impaired and hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in vivo were exaggerated in offspring of RDP. This pulmonary vascular dysfunction was associated with altered lung DNA methylation. Administration of the histone deacetylase inhibitors butyrate and trichostatin A to offspring of RDP normalized pulmonary DNA methylation and vascular function. Finally, administration of the nitroxide Tempol to the mother during RDP prevented vascular dysfunction and dysmethylation in the offspring. These findings demonstrate that in mice undernutrition during gestation induces pulmonary vascular dysfunction in the offspring by an epigenetic mechanism. A similar mechanism may be involved in the fetal programming of vascular dysfunction in humans.

36 EFFECT OF DNA METHYLTRANSFERASE INHIBITOR, RG108, ON IN VITRO DEVELOPMENT AND ntES ESTABLISHMENT RATE IN CLONED MOUSE EMBRYOS

2012 ◽  
Vol 24 (1) ◽  
pp. 130 ◽  
Author(s):  
C. Li ◽  
Y. Terashita ◽  
M. Tokoro ◽  
S. Wakayama ◽  
T. Wakayama
Keyword(s):  
Dna Methylation ◽  
Histone Acetylation ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Blastocyst Stage ◽  
Control Group ◽  
Cloning Efficiency ◽  
Dna Methyltransferase Inhibitor

Somatic cell nuclear transfer technique increased expectations among many for its potential to advance the regenerative therapy field. Cloned embryos, however, exhibit several epigenetic abnormalities, such as low histone acetylation or high DNA methylation levels compared with normal fertilized embryos. Therefore, increasing histone acetylation or reducing DNA methylation levels in cloned embryos using chemical treatments may improve cloning efficiency. We recently succeeded in improving the success rate of mouse cloning by using class IIb histone deacetylase inhibitors, such as trichostatin A (TSA), scriptaid and suberoylanilide hydroxamic acid. It has also been reported that 5-aza-2′-deoxycytidine, a DNA methyltransferase inhibitor that is a chemical analogue of cytidine, inhibits the potential of embryos to develop into blastocysts and later to fetuses. In the present study, another DNA methyltransferase inhibitor RG108, which is thought to strongly interact with the DNMT1 active site to inhibit DNMT1 activity, was used to examine whether it could improve cloning efficiency. To determine the effects of RG108, cloned embryos were treated with 100 to 500 μM RG108. When cloned embryos were treated at the 1-cell stage (from artificial activation to 10 h, n = 219), the cloning efficiency was similar to the control group (8.2 vs 10.8%). On the other hand, when 500 μM RG108 was added to the culture medium from the 2-cell to morula/blastocyst stage (n = 113), although the developmental rate to blastocyst stage did not change significantly (79.6% vs 72.3%), higher Oct3/4 expression and more ICM cells were observed compared with non-treated, control cloned embryos. Moreover, we tried to establish ES cell lines from those cloned embryos and 11 ntES lines were generated from 21 blastocysts, which was higher than that of control (6 ntES cell lines from 20 blastocysts). All ntES lines showed AP staining positively. This finding showed that the quality of cloned mouse blastocysts increased when treated with a DNA methyltransferase inhibitor, suggesting a possible means for improving cloning efficiency in the future.

scholarly journals Evidence of Endogenous Mu Opioid Receptor Regulation by Epigenetic Control of the Promoters

2007 ◽  
Vol 27 (13) ◽  
pp. 4720-4736 ◽  
Author(s):  
Cheol Kyu Hwang ◽  
Kyu Young Song ◽  
Chun Sung Kim ◽  
Hack Sun Choi ◽  
Xiao-Hong Guo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Opioid Receptor ◽  
Promoter Region ◽  
Histone Deacetylase Inhibitors ◽  
Mu Opioid Receptor ◽  
Histone Deacetylation ◽  
Epigenetic Mechanism ◽  
Proximal Promoter ◽  
Mu Opioid

ABSTRACT The pharmacological effect of morphine as a painkiller is mediated mainly via the mu opioid receptor (MOR) and is dependent on the number of MORs in the cell surface membrane. While several studies have reported that the MOR gene is regulated by various cis- and trans-acting factors, many questions remain unanswered regarding in vivo regulation. The present study shows that epigenetic silencing and activation of the MOR gene are achieved through coordinated regulation at both the histone and DNA levels. In P19 mouse embryonal carcinoma cells, expression of the MOR was greatly increased after neuronal differentiation. MOR expression could also be induced by a demethylating agent (5′-aza-2′-deoxycytidine) or histone deacetylase inhibitors in the P19 cells, suggesting involvement of DNA methylation and histone deacetylation for MOR gene silencing. Analysis of CpG DNA methylation revealed that the proximal promoter region was unmethylated in differentiated cells compared to its hypermethylation in undifferentiated cells. In contrast, the methylation of other regions was not changed in either cell type. Similar methylation patterns were observed in the mouse brain. In vitro methylation of the MOR promoters suppressed promoter activity in the reporter assay. Upon differentiation, the in vivo interaction of MeCP2 was reduced in the MOR promoter region, coincident with histone modifications that are relevant to active transcription. When MeCP2 was disrupted using MeCP2 small interfering RNA, the endogenous MOR gene was increased. These data suggest that DNA methylation is closely linked to the MeCP2-mediated chromatin structure of the MOR gene. Here, we propose that an epigenetic mechanism consisting of DNA methylation and chromatin modification underlies the cell stage-specific mechanism of MOR gene expression.

scholarly journals Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation

2021 ◽  
Vol 22 (16) ◽  
pp. 8622
Author(s):  
Xiangqun Hu ◽  
Lubo Zhang
Keyword(s):  
Blood Flow ◽  
Hormonal Regulation ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Well Being ◽  
Normal Pregnancy ◽  
Functional Adaptation ◽  
Vasoactive Factors ◽  
Uteroplacental Blood Flow ◽  
Underlying Mechanisms

Uteroplacental blood flow increases as pregnancy advances. Adequate supply of nutrients and oxygen carried by uteroplacental blood flow is essential for the well-being of the mother and growth/development of the fetus. The uteroplacental hemodynamic change is accomplished primarily through uterine vascular adaptation, involving hormonal regulation of myogenic tone, vasoreactivity, release of vasoactive factors and others, in addition to the remodeling of spiral arteries. In preeclampsia, hormonal and angiogenic imbalance, proinflammatory cytokines and autoantibodies cause dysfunction of both endothelium and vascular smooth muscle cells of the uteroplacental vasculature. Consequently, the vascular dysfunction leads to increased vascular resistance and reduced blood flow in the uteroplacental circulation. In this article, the (mal)adaptation of uteroplacental vascular function in normal pregnancy and preeclampsia and underlying mechanisms are reviewed.

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.

Downregulation of Mir-22 in ALL Cells Is Associated with the Accumulation of Histone Modification but Independent of DNA Methylation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3464-3464
Author(s):  
Xiaoqing Li ◽  
Jun Liu ◽  
Rui Zhou ◽  
Shi Huang ◽  
Xian-Ming Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone Modification ◽  
Conflicts Of Interest ◽  
Trichostatin A ◽  
Lymphoblastic Leukemia ◽  
Methylation Status ◽  
Epigenetic Mechanism ◽  
Promoter Element ◽  
Dna Hypermethylation ◽  
Number Of Patients

Abstract Abstract 3464 Poster Board III-352 MicroRNA-22 is one of the miRNAs frequently downregulated in human ALL cells and may play an important anti-tumor role in normal hematopoiesis. Histone modification and DNA methylation can have different roles in gene silencing in cancer. To investigate whether histone modifications would contribute to the dysregulation of miRNA-22 in acute lymphoblastic leukemia (ALL), the effect of a histone deacetylase inhibitor, trichostatin A (TSA), on miRNA-22 expression of primary ALL cells was analyzed by real-time PCR. The total number of patients included to this study is 33, including 26 samples of leukemia (18 of ALL and 8 of acute myeloid leukemia) and 7 normal controls. All patient blood samples were collected at the time of diagnosis. We detected a lower expression of pri-miR-22 in PMBCs from ALL patients compared with that from the health volunteers. Treatment with TSA significantly increased pri-miR-22 expression in PMBCs from ALL patients, but not in cells from the health volunteers. Whereas PMBCs from ALL patients and AML patients showed comparable levels of pri-miR-22. TSA treatment had no effect on pri-miR-22 expression in PMBCs from AML patients, suggesting TSA-mediated upregulation of miR-22 transcription in ALL but not AML malignant cells. Moreover, we used MPS assay to analyze the methylation status at the promoter element of miR-22 gene in primary human specimens. No DNA hypermethylation was detected in PMBCs from the health volunteers and patients with either ALL or AML. These data provide further evidence that miR-22 silencing in ALL cells may be DNA methylation-independent. In contrast, accumulation of the repressive histone marker H3K27 trimethylation (H3K27triM) was indentified around the transcriptional start point of the gene, which reduced by TSA treatment. In conclusion, we showed that histone modification is involved in miRNA dysregulation in human ALL cells. Specifically, the silencing of miR-22 in ALL cells is associated with the accumulation of histone modification in its promoter element of miR-22 gene but independent of DNA methylation. The accumulation of H3K27triM may be a novel epigenetic mechanism for miR-22 silencing in ALL. Disclosures No relevant conflicts of interest to declare.

Abstract 15715: Dna Methylation of Genes Involved in Inflammation Correlates With Cardiometabolic Function in Morbidly Obese Adults

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Mohamed M Ali ◽  
Chandra Hassan ◽  
Mario Masrur ◽  
Francesco Bianco ◽  
Patrice Frederick ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vascular Function ◽  
Multiple Testing ◽  
Vascular Dysfunction ◽  
Morbidly Obese ◽  
No Production ◽  
Dna Hypomethylation ◽  
Obese Adults ◽  
Downstream Target ◽  
Differentially Methylated Genes

Obesity is a major risk factor for cardiovascular disease. We previously demonstrated impaired vascular function that correlated with global DNA hypomethylation in adipose tissue (AT) isolated from obese adults (OB). Blood-detected epigenetic profiles may serve as non-invasive clinically relevant biomarkers and stand as an unexploited precision medicine reserve. Hypothesis: We hypothesized a contributing role of DNA methylation to systemic inflammation in OB subjects compared to lean controls (CON). We also explored the correlation between these methylation profiles and cardiometabolic measurements. Methods: We obtained blood and AT samples from bariatric patients (n=24; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and CON adults (n=24; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for flow-induced dilation (FID), nitric oxide (NO) and reactive oxygen species (ROS) production. Brachial artery flow-mediated dilation (FMD) was measured via Doppler ultrasound. Promoter methylation of 94 genes involved in inflammation and autoimmunity (EpiTect Methyl II PCR Arrays) were analyzed in whole-blood DNA in relation to vascular function and cardiometabolic risk factors. Results: 70% of genes had a higher methylated fraction in CON compare to only 28% in OB subjects. After correction for multiple testing, 28 genes were significantly hypermethylated in CON compared to OB; on top of these genes are CXCL1, CXCL12, CXCL6, EGR1, HDAC4, IGF2BP2, IL12A, IL12B, and IL17RA. Ten of these genes had significantly higher mRNA in OB compared to CON indicating the functional impact of such signals on gene transcription; on top of these genes are CXCL6, TLR5, IL6ST, IL15RA, and HDAC4. Methylation % of differentially methylated genes inversely correlated with BMI, total fat %, visceral fat%, blood pressure, fasting plasma insulin, serum IL6 and CRP (C-reactive protein), arteriolar ROS, and alcohol consumption and positive correlations with lean %, HDL, plasma folate and vitamin B12, arteriolar FID and NO production, and brachial FMD. Conclusions: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation. A downstream target for this pathway could reside in endothelial cells resulting in vascular dysfunction

Tobacco-associated pulmonary vascular dysfunction in smokers: role of the ET-1 pathway

2011 ◽  
Vol 300 (6) ◽  
pp. L831-L839 ◽  
Author(s):  
Priscilla Henno ◽  
Jean-François Boitiaux ◽  
Benoit Douvry ◽  
Aurélie Cazes ◽  
Marilyne Lévy ◽  
...  
Keyword(s):  
Tobacco Smoking ◽  
Potential Role ◽  
Vascular Dysfunction ◽  
Subsequent Development ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Endothelium ◽  
Endothelin 1 ◽  
Underlying Mechanisms ◽  
Pulmonary Vascular Dysfunction

Pulmonary vascular remodeling and dysfunction associated to tobacco smoking might pave the way for the subsequent development of pulmonary hypertension. Its prognosis is dreadful and its underlying mechanisms are so far largely unknown in humans. To assess the potential role of endothelin-1 and its receptors in smokers' pulmonary artery vasoactive properties. Endothelium-dependent vasodilation to ACh was assessed in pulmonary vascular rings from 34 smokers and compared with that of 10 nonsmokers. The effects of ET-A (BQ 123) or ET-B (BQ 788) blockers and that of an ET-B activator (sarafotoxin) were evaluated. Endothelin-1 was quantitated by ELISA. Expression of its receptors was quantitated by Western blotting. Smokers exhibited an impaired pulmonary endothelium-dependent vasodilation compared with nonsmokers ( P < 0.01). In the former group, 8 of 34 subjects exhibited a marked endothelial dysfunction (ED+) whereas 26 (ED−) ( P < 10−4) displayed a vasorelaxation to ACh that was comparable to that of nonsmokers. In ED+ subjects, ET-A was overexpressed ( P < 0.05) and inversely correlated ( P < 10−2) with the response to ACh. Sarafotoxin significantly improved vasodilation in all subjects ( P < 10−2). In conclusion, tobacco smoking is associated to an impaired pulmonary vasorelaxation at least partly mediated by an ET-1/ET-A-dependent dysfunction.

Increased myogenic tone in 7-month-old adult male but not female offspring from rat dams exposed to hypoxia during pregnancy

2005 ◽  
Vol 289 (2) ◽  
pp. H674-H682 ◽  
Author(s):  
D. G. Hemmings ◽  
S. J. Williams ◽  
S. T. Davidge
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Female Offspring ◽  
Growth Restriction ◽  
Mesenteric Arteries ◽  
Adult Offspring ◽  
Dependent Manner ◽  
Maternal Undernutrition ◽  
Myogenic Responses ◽  
Prostaglandin H

Intrauterine growth restriction (IUGR) increases the risk of cardiovascular disease later in life. Vascular dysfunction occurs in adult offspring from animal models of IUGR including maternal undernutrition, but the influence of reduced fetal oxygen supply on adult vascular function is unclear. Myogenic responses, essential for vascular tone regulation, have not been evaluated in these offspring. We hypothesized that 7-mo-old offspring from hypoxic (12% O2; H) or nutrient-restricted (40% of control; NR) rat dams would show greater myogenic responses than their 4-mo-old littermates or control (C) offspring through impaired modulation by vasodilators. Growth restriction occurred in male H ( P < 0.01), male NR ( P < 0.01), and female NR ( P < 0.02), but not female H, offspring. Myogenic responses in mesenteric arteries from males but not females were increased at 7 mo in H ( P < 0.01) and NR ( P < 0.05) vs. C offspring. There was less modulation of myogenic responses after inhibition of nitric oxide synthase ( P < 0.05), prostaglandin H synthase ( P < 0.005), or both enzymes ( P < 0.001) in arteries from 7-mo male H vs. C offspring. Thus reduced vasodilator modulation may explain elevated myogenic responses in 7-mo male H offspring. In contrast, there was increased modulation of myogenic responses in arteries from 7-mo female H vs. C or NR offspring after inhibition of both enzymes ( P < 0.05). Thus increased vasodilator modulation may maintain myogenic responses in female H offspring at control levels. In summary, vascular responses in adult offspring from adverse intrauterine environments are impaired in a gender-specific, age-dependent, and maternal insult-dependent manner, with males more profoundly affected.

scholarly journals Roles and Mechanisms of DNA Methylation in Vascular Aging and Related Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Hui Xu ◽  
Shuang Li ◽  
You-Shuo Liu
Keyword(s):  
Dna Methylation ◽  
Aging Process ◽  
Vascular Dysfunction ◽  
Structure And Function ◽  
Epigenetic Mechanism ◽  
Vascular Aging ◽  
Reversible Process ◽  
Therapeutic Drugs ◽  
And Function ◽  
Vascular Cell Senescence

Vascular aging is a pivotal risk factor promoting vascular dysfunction, the development and progression of vascular aging-related diseases. The structure and function of endothelial cells (ECs), vascular smooth muscle cells (VSMCs), fibroblasts, and macrophages are disrupted during the aging process, causing vascular cell senescence as well as vascular dysfunction. DNA methylation, an epigenetic mechanism, involves the alteration of gene transcription without changing the DNA sequence. It is a dynamically reversible process modulated by methyltransferases and demethyltransferases. Emerging evidence reveals that DNA methylation is implicated in the vascular aging process and plays a central role in regulating vascular aging-related diseases. In this review, we seek to clarify the mechanisms of DNA methylation in modulating ECs, VSMCs, fibroblasts, and macrophages functions and primarily focus on the connection between DNA methylation and vascular aging-related diseases. Therefore, we represent many vascular aging-related genes which are modulated by DNA methylation. Besides, we concentrate on the potential clinical application of DNA methylation to serve as a reliable diagnostic tool and DNA methylation-based therapeutic drugs for vascular aging-related diseases.

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