Extrauterine growth restriction on pulmonary vascular endothelial dysfunction in adult male rats

Abstract

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.

Postnatal growth restriction augments oxygen-induced pulmonary hypertension in a neonatal rat model of bronchopulmonary dysplasia

“…Our data indicate that PNGR affected both markers of lung vascular development and amplified the effects of oxygen. PNGR under normoxic conditions significantly increased PA medial wall thickness in male rats at 9 wk of age (20), and here we report a significant increase in medial wall thickness at 2 wk of age regardless of gender. In contrast, while oxygen induced a significant increase in mean alveolar area and a significant decrease in radial alveolar count, PNGR did not have any detectable effect on alveolarization under normoxic or hyperoxic conditions.…”

“…We found that PNGR induced PH and RVH at 14 d even without exposure to hyperoxia, and amplified the effect of hyperoxia on RVH, suggesting that distinct mechanisms triggered by each insult could account for the cumulative increase. A recent study using a similar model of PNGR identified an increase in pulmonary arterial pressure and increased Fulton's index in male rats at 9 wk of age (20). Our data indicate that increased pulmonary arterial pressure and RVH are manifest at 2 wk of age in both males and females.…”

Epigenetics of Notch1 regulation in pulmonary microvascular rarefaction following extrauterine growth restriction

“…Infants with a transient perinatal insult may develop pulmonary arterial hypertension early in postnatal life [ 7 ], or be predisposed to an increased risk of developing this disorder later in life [ 8 ]. In animal studies, we recently addressed a strong association between malnutrition during different critical windows and impaired pulmonary vascular function in adulthood [ 9 – 11 ]. Intrauterine growth restriction (IUGR) resulted in aggravated hypoxic pulmonary hypertension and vascular remodeling [ 10 ], whereas extrauterine growth restriction (EUGR) rats developed elevated pulmonary arterial pressure (PAP) in the absence of a second-hit [ 11 ].…”

“…In animal studies, we recently addressed a strong association between malnutrition during different critical windows and impaired pulmonary vascular function in adulthood [ 9 – 11 ]. Intrauterine growth restriction (IUGR) resulted in aggravated hypoxic pulmonary hypertension and vascular remodeling [ 10 ], whereas extrauterine growth restriction (EUGR) rats developed elevated pulmonary arterial pressure (PAP) in the absence of a second-hit [ 11 ]. Although we and other study [ 12 ] provide the evidence about developmental plasticity of pulmonary vasculature, the precise mechanism is still unknown.…”

“…Epigenetic regulation, including histone modification and DNA methylation, plays a major part in the developmental origins of adult diseases [ 25 , 26 ]. Our recent studies revealed both IUGR and EUGR induced histone modifications in the vascular tone regulators, endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) [ 10 , 11 ]. In addition, expression of key factors, peroxisome proliferator-activated receptor gamma (PPARγ) and insulin-like growth factor-1 (IGF-1), were affected by DNA methylation and histone modification following EUGR [ 11 ].…”