BackgroundAccumulating evidence reveals that intrauterine growth retardation (IUGR) can cause varying degrees of pulmonary arterial hypertension (PAH) later in life. Moreover, epigenetics plays an important role in the fetal origin of adult disease. The goal of this study was to investigate the role of epigenetics in the development of PAH following IUGR.MethodsThe IUGR rats were established by maternal undernutrition during pregnancy. Pulmonary vascular endothelial cells (PVEC) were isolated from the rat lungs by magnetic-activated cell sorting (MACS). We investigated epigenetic regulation of the endothelin-1 (ET-1) gene in PVEC of 1-day and 6-week IUGR rats, and response of IUGR rats to hypoxia.ResultsThe maternal nutrient restriction increased the histone acetylation and hypoxia inducible factor-1α (HIF-1α) binding levels in the ET-1 gene promoter of PVEC in IUGR newborn rats, and continued up to 6 weeks after birth. These epigenetic changes could result in an IUGR rat being highly sensitive to hypoxia later in life, causing more significant PAH or pulmonary vascular remodeling.ConclusionsThese findings suggest that epigenetics is closely associated with the development of hypoxic PAH following IUGR, further providing a new insight for improved prevention and treatment of IUGR-related PAH.

Objective:Early postnatal life is considered as a critical time window for the determination of long-term metabolic states and organ functions. Extrauterine growth restriction (EUGR) causes the development of adult-onset chronic diseases, including pulmonary hypertension. However, the effects of nutritional disadvantages during the early postnatal period on pulmonary vascular consequences in later life are not fully understood. Our study was designed to test whether epigenetics dysregulation mediates the cellular memory of this early postnatal event.Methods and results:To test this hypothesis, we isolated pulmonary vascular endothelial cells by magnetic-activated cell sorting from EUGR and control rats. A postnatal insult, nutritional restriction-induced EUGR caused development of an increased pulmonary artery pressure at 9 weeks of age in male Sprague–Dawley rats. Methyl-DNA immune precipitation chip, genome-scale mapping studies to search for differentially methylated loci between control and EUGR rats, revealed significant difference in cytosine methylation between EUGR and control rats. EUGR changes the cytosine methylation at approximately 500 loci in male rats at 9 weeks of age, preceding the development of pulmonary hypertension and these represent the candidate loci for mediating the pathogenesis of pulmonary vascular disease that occurs later in life. Gene ontology analysis on differentially methylated genes showed that hypermethylated genes in EUGR are vascular development-associated genes and hypomethylated genes in EUGR are late-differentiation-associated and signal transduction genes. We validated candidate dysregulated loci with the quantitative assays of cytosine methylation and gene expressions.Conclusion:These results demonstrate that epigenetics dysregulation is a strong mechanism for propagating the cellular memory of early postnatal events, causing changes in the expression of genes and long-term susceptibility to pulmonary hypertension, and further providing a new insight into the prevention and treatment of EUGR-related pulmonary hypertension.

Chronic hypoxia pulmonary hypertension (CH-PHT) in adulthood is likely to be of fetal origin following intrauterine growth retardation (IUGR). Oxygen (O2)-sensitive voltage-gated potassium channels (Kv channels) in resistance pulmonary artery smooth muscle cells (PASMCs) play an important role in scaling pulmonary artery (PA) pressure. Expression and functional changes of Kv channels are determined, in part, by embryonic development. We hypothesized that O2-sensitive Kv channels play an important role in exaggerated CH-PHT following IUGR. We established a rat model of IUGR by restricting maternal food during the entire pregnancy and exposed IUGR rats and their agematched controls aged 12 wk to hypoxia for 2 wk. We found that hypoxia exposure significantly induced increased PA pressure and thicker smooth muscle layer in the IUGR group relative to controls. We compared the constriction of the resistance PA to inhibitors of K ϩ channels, 4-aminopyridine (4-AP), tetraethylammonium, and BaCl2. Despite the thickness of the smooth muscle layer, the constriction to 4-AP was significantly reduced in the IUGR group exposed to hypoxia. Consistent with these changes in pulmonary vascular reactivity, 2 wk of hypoxia induced weaker 4-AP-sensitive Kv currents in a single IUGR PASMC. Moreover, after 2 wk of hypoxia, Kv1.5 expression in resistance PAs decreased significantly in the IUGR group. Overexpression of Kv1.5 in cultured PASMCs could offset hypoxia-induced cell proliferation and hypoxia-inhibited Kv currents in the IUGR group. These results suggest that the inhibited expression of Kv1.5 in PASMCs contribute to the development of exaggerated CH-PHT in IUGR rats during adulthood. chronic hypoxic pulmonary hypertension; intrauterine growth retardation; voltage-gated potassium channel; pulmonary artery smooth muscle cell RECENTLY, INTRAUTERINE GROWTH RETARDATION (IUGR) has been considered to be associated with the fetal origin of adult disease (4). IUGR is defined as having a birth weight below the 10th percentile of the corresponding gestational age (25). Several studies have demonstrated that IUGR predicts the risk of developing various adult diseases, including obesity, Type 2 diabetes, and hypertension (12, 33). Its biological risk factors include intrauterine malnutrition and intrauterine hypoxia. Intrauterine hypoxia may also have a persistent effect on the infant pulmonary vasculature, which, when activated in adult life, predisposes to a pathological response (32). Similar to that in our recent study, exaggerated pulmonary hypertension (PHT) was observed because of exposure to chronic hypoxia in adult IUGR male rats. Additionally, intrauterine malnutrition plays an important role during this process (39). Another study showed that PHT of offspring in adulthood is associated with maternal undernutrition during pregnancy, although the offspring do not exhibit low birth weight (30). Moreover, maternal protein restriction during pregnancy limits fetal pulmonary development, a finding that may increase the susceptibility ...