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Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms.
MedLine Citation:
PMID:  21536851     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Insults during the fetal period predispose the offspring to systemic cardiovascular disease, but little is known on 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-week 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.
Authors:
Emrush Rexhaj; Jonathan Bloch; Pierre-Yves Jayet; Stefano Rimoldi; Pierre Dessen; Caroline Mathieux; Jean-Francois Tolsa; Pascal Nicod; Urs Scherrer; Claudio Sartori
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-5-2
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  -     ISSN:  1522-1539     ISO Abbreviation:  -     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-5-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1Centre Hospitalier Universitaire Vaudois.
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