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

Abstract

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.

Mice generated by in vitro fertilization exhibit vascular dysfunction and shortened life span

“…There is evidence that ART may alter epigenetic mechanisms (14,15). These alterations may be transmitted to the next generation (13,16,17). To test for this possibility, we examined vascular function and arterial blood pressure in male offspring generated by mating male ART mice with control females.…”

“…To test this hypothesis, we compared vascular function between mice born after implantation of 2 cell embryos and blastocysts. Finally, in mice, epigenetic mechanism are involved in the fetal programming of vascular dysfunction (13), and in humans, the prevalence of very rare diseases caused by epigenetic mechanisms is increased in ART (14,15). Epigenetic alterations may be transmitted to the next generation (13,16,17).…”

Effects of Oxidative Stress on Vascular Reactivity in the Offspring of Protein-Restricted Stroke-Prone Spontaneously Hypertensive Rats

“…Indeed, a pulmonary vascular dysfunction in the offspring of dams fed a restricted diet has been prevented by administering either a histone deacetylase inhibitor (butyrate) or a nitroxide (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, Tempol). 8) However, it is still unclear how ROS may induce hypertension or vascular injury in the offspring of protein-restricted dams. NADPH oxidase is the major source of ROS and is highly expressed in vascular endothelial cells and leukocytes.…”

Kidney Disease and Perinatal Programming of Arterial Hypertension: the Results of Experimental Researches

“…В этих экспе-риментах установлено, что повреждение оксидативным стрессом почек крыс самцов было более выражено, чем у самок [67]. Предполагается, что оксидативное повреж-дение может приводить к эндотелиальной дисфункции, которая и реализуется в виде АГ [68].…”