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

Rexhaj, Emrush; Bloch, Jonathan; Jayet, Pierre-Yves; Rimoldi, Stefano F.; Dessen, Pierre; Mathieu, Caroline; Tolsa, Jean-François; Nicod, Pascal; Scherrer, Urs; Sartori, Claudio (2011). Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms. American journal of physiology - heart and circulatory physiology, 301(1), H247-H252. American Physiological Society 10.1152/ajpheart.01309.2010

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology

UniBE Contributor:

Rimoldi, Stefano

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0363-6135

Publisher:

American Physiological Society

Language:

English

Submitter:

Stefano Rimoldi

Date Deposited:

11 Jul 2014 15:41

Last Modified:

11 Jul 2014 15:41

Publisher DOI:

10.1152/ajpheart.01309.2010

PubMed ID:

21536851

URI:

https://boris.unibe.ch/id/eprint/43132

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