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Extrauterine growth restriction on pulmonary vascular endothelial dysfunction in adult male rats: the role of epigenetic mechanisms.

Zhang L, Tang L, Wei J, Lao L, Gu W, Hu Q, Lv Y, Fu L, Du L - J. Hypertens. (2014)

Bottom Line: Early postnatal life is considered as a critical time window for the determination of long-term metabolic states and organ functions.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.

View Article: PubMed Central - PubMed

Affiliation: aDepartment of Neonatology bDepartment of Pathology, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.

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.

No MeSH data available.


Related in: MedlinePlus

Quantitative RT-PCR shows the change of eNOS, PPARγ and IGF-1 genes in mRNA expression. Average log2 ratio (± SEM) of EUGR expression data relative to controls was calculated for each gene. n = 6–8, ∗P < 0.05. eNOS, endothelial nitric oxide synthase; IGF-1, insulin-like growth factor-1; PPARγ, peroxisome proliferator-activated receptor gamma.
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Figure 3: Quantitative RT-PCR shows the change of eNOS, PPARγ and IGF-1 genes in mRNA expression. Average log2 ratio (± SEM) of EUGR expression data relative to controls was calculated for each gene. n = 6–8, ∗P < 0.05. eNOS, endothelial nitric oxide synthase; IGF-1, insulin-like growth factor-1; PPARγ, peroxisome proliferator-activated receptor gamma.

Mentions: The eNOS expression level in the EUGR male rats was lower than that in the controls, and there was a statistically significant difference between the two groups (P = 0.032; Fig. 2g). Similar to the protein expression pattern, the eNOS mRNA expression showed a similar trend (Fig. 3). These results indicate that the decreased eNOS level of EUGR rats might be responsible for the increased PAP and pulmonary vascular remodeling changes.


Extrauterine growth restriction on pulmonary vascular endothelial dysfunction in adult male rats: the role of epigenetic mechanisms.

Zhang L, Tang L, Wei J, Lao L, Gu W, Hu Q, Lv Y, Fu L, Du L - J. Hypertens. (2014)

Quantitative RT-PCR shows the change of eNOS, PPARγ and IGF-1 genes in mRNA expression. Average log2 ratio (± SEM) of EUGR expression data relative to controls was calculated for each gene. n = 6–8, ∗P < 0.05. eNOS, endothelial nitric oxide synthase; IGF-1, insulin-like growth factor-1; PPARγ, peroxisome proliferator-activated receptor gamma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4222616&req=5

Figure 3: Quantitative RT-PCR shows the change of eNOS, PPARγ and IGF-1 genes in mRNA expression. Average log2 ratio (± SEM) of EUGR expression data relative to controls was calculated for each gene. n = 6–8, ∗P < 0.05. eNOS, endothelial nitric oxide synthase; IGF-1, insulin-like growth factor-1; PPARγ, peroxisome proliferator-activated receptor gamma.
Mentions: The eNOS expression level in the EUGR male rats was lower than that in the controls, and there was a statistically significant difference between the two groups (P = 0.032; Fig. 2g). Similar to the protein expression pattern, the eNOS mRNA expression showed a similar trend (Fig. 3). These results indicate that the decreased eNOS level of EUGR rats might be responsible for the increased PAP and pulmonary vascular remodeling changes.

Bottom Line: Early postnatal life is considered as a critical time window for the determination of long-term metabolic states and organ functions.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.

View Article: PubMed Central - PubMed

Affiliation: aDepartment of Neonatology bDepartment of Pathology, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.

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.

No MeSH data available.


Related in: MedlinePlus