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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

EUGR male rats developed increased pulmonary artery pressure at 9 weeks of age. Pulmonary artery pressure (PAP; a) and right ventricle-to-left ventricle and septum (RV to LV + S) weight ratio (b) in EUGR and control rats are shown at 9 weeks of age. Representative lung histological sections of controls (c) and EUGR (d) are shown, demonstrating hypertrophy of the arterial medial wall induced by EUGR. Note significant medial thickness (d), and the prominent obstructive intimal thickening at the level of small arteries and arterioles was observed in EUGR group (200×). The bar graph represents the %vascular medial wall diameter (e) and percentage vascular medial wall area (f) of the small pulmonary arteries. (g) eNOS protein expression in PVEC. Western blots for eNOS utilize beta-actin as an internal control. Note that eNOS protein level in EUGR was significantly lower than that in the control (n = 5–6; ∗P < 0.05). eNOS, endothelial nitric oxide synthase; EUGR, extrauterine growth restriction; PVECs, pulmonary vascular endothelial cells.
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Figure 2: EUGR male rats developed increased pulmonary artery pressure at 9 weeks of age. Pulmonary artery pressure (PAP; a) and right ventricle-to-left ventricle and septum (RV to LV + S) weight ratio (b) in EUGR and control rats are shown at 9 weeks of age. Representative lung histological sections of controls (c) and EUGR (d) are shown, demonstrating hypertrophy of the arterial medial wall induced by EUGR. Note significant medial thickness (d), and the prominent obstructive intimal thickening at the level of small arteries and arterioles was observed in EUGR group (200×). The bar graph represents the %vascular medial wall diameter (e) and percentage vascular medial wall area (f) of the small pulmonary arteries. (g) eNOS protein expression in PVEC. Western blots for eNOS utilize beta-actin as an internal control. Note that eNOS protein level in EUGR was significantly lower than that in the control (n = 5–6; ∗P < 0.05). eNOS, endothelial nitric oxide synthase; EUGR, extrauterine growth restriction; PVECs, pulmonary vascular endothelial cells.

Mentions: We next examined the right ventricular systolic pressure (RVSP) and the pulmonary artery pressure (PAP) at 63-day-old male rats. We found that EUGR rats developed increased RVSP and PAP compared with controls to some degrees. PAP was 19.23 ± 1.34 mmHg in control rats vs. 26.69 ± 2.51 mmHg in EUGR rats (P < 0.05; Fig. 2a). RVSP was 14.53 ± 2.34 mmHg in control rats vs. 19.69 ± 2.11 mmHg in EUGR rats (P < 0.05). And, right ventricle-to-left ventricle and septum (RV to LV + S) weight ratio was significantly higher in EUGR compared with control rats (Fig. 2b).


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)

EUGR male rats developed increased pulmonary artery pressure at 9 weeks of age. Pulmonary artery pressure (PAP; a) and right ventricle-to-left ventricle and septum (RV to LV + S) weight ratio (b) in EUGR and control rats are shown at 9 weeks of age. Representative lung histological sections of controls (c) and EUGR (d) are shown, demonstrating hypertrophy of the arterial medial wall induced by EUGR. Note significant medial thickness (d), and the prominent obstructive intimal thickening at the level of small arteries and arterioles was observed in EUGR group (200×). The bar graph represents the %vascular medial wall diameter (e) and percentage vascular medial wall area (f) of the small pulmonary arteries. (g) eNOS protein expression in PVEC. Western blots for eNOS utilize beta-actin as an internal control. Note that eNOS protein level in EUGR was significantly lower than that in the control (n = 5–6; ∗P < 0.05). eNOS, endothelial nitric oxide synthase; EUGR, extrauterine growth restriction; PVECs, pulmonary vascular endothelial cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: EUGR male rats developed increased pulmonary artery pressure at 9 weeks of age. Pulmonary artery pressure (PAP; a) and right ventricle-to-left ventricle and septum (RV to LV + S) weight ratio (b) in EUGR and control rats are shown at 9 weeks of age. Representative lung histological sections of controls (c) and EUGR (d) are shown, demonstrating hypertrophy of the arterial medial wall induced by EUGR. Note significant medial thickness (d), and the prominent obstructive intimal thickening at the level of small arteries and arterioles was observed in EUGR group (200×). The bar graph represents the %vascular medial wall diameter (e) and percentage vascular medial wall area (f) of the small pulmonary arteries. (g) eNOS protein expression in PVEC. Western blots for eNOS utilize beta-actin as an internal control. Note that eNOS protein level in EUGR was significantly lower than that in the control (n = 5–6; ∗P < 0.05). eNOS, endothelial nitric oxide synthase; EUGR, extrauterine growth restriction; PVECs, pulmonary vascular endothelial cells.
Mentions: We next examined the right ventricular systolic pressure (RVSP) and the pulmonary artery pressure (PAP) at 63-day-old male rats. We found that EUGR rats developed increased RVSP and PAP compared with controls to some degrees. PAP was 19.23 ± 1.34 mmHg in control rats vs. 26.69 ± 2.51 mmHg in EUGR rats (P < 0.05; Fig. 2a). RVSP was 14.53 ± 2.34 mmHg in control rats vs. 19.69 ± 2.11 mmHg in EUGR rats (P < 0.05). And, right ventricle-to-left ventricle and septum (RV to LV + S) weight ratio was significantly higher in EUGR compared with control rats (Fig. 2b).

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