Dietary Protein Restriction in Pregnancy Induces Hypertension and Vascular Defects in Rat Male Offspring

Brawley, L; Itoh, Shigeru; Torrens, Christopher; Barker, A C; Bertram, C.; Poston, Lucilla; Hanson, Mark A.

doi:10.1203/01.pdr.0000065731.00639.02

Cited by 227 publications

(218 citation statements)

References 66 publications

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“…Rats exposed during gestation to maternal energy-or proteinrestricted diets have an increased incidence of endothelial dysfunction and hypertension. [5][6][7][8] Similar outcomes have been observed in the offspring of rats fed a high-fat diet during pregnancy. 9,10 Whether there is any relation in humans between characteristics of maternal diet during pregnancy and atherogenesis is not known, although the observation that maternal hypercholesterolemia during pregnancy is linked with faster progression of early atherosclerotic lesions in children suggests that the type and quantity of fat in the maternal diet may play a role in fetal atherogenesis.…”

supporting

confidence: 69%

Maternal Diet During Pregnancy and Carotid Intima–Media Thickness in Children

Gale

Jiang

Robinson

et al. 2006

ATVB

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Objective-Autopsy studies show that intimal lipid accumulations in arteries are often present at birth, suggesting that the prenatal environment plays a role in the pathogenesis of atherosclerosis. In animal models, a restricted or unbalanced maternal diet during gestation can influence susceptibility to atherosclerosis, but the relation in humans between maternal diet during pregnancy and atherogenesis is unknown. Methods and Results-We measured carotid intima-media thickness (IMT) in 216 nine-year-old children whose mothers had participated in a study of nutrition during pregnancy. IMT was greater in boys, in children who were heavier, in those with higher systolic blood pressure, and in those who took less exercise. Increased IMT was associated with a lower maternal energy intake in early (Pϭ0.029) or late (Pϭ0.006) pregnancy, after adjustment for these factors. Mean IMT of children whose mothers were in the lowest quarter of the distribution of energy intake in late pregnancy was 0.027 mm (95% confidence interval, 0.004 to 0.049) greater than that of those whose mothers were in the highest quarter of the distribution. Conclusion-Lower maternal energy intake during pregnancy may increase the susceptibility to atherogenesis of the child. Key Words: carotid arteries Ⅲ atherosclerosis Ⅲ pregnancy Ⅲ diet Ⅲ children A therosclerosis is a progressive condition that begins early in life. Fatty streaks and intimal thickenings, the initial lesions of atherogenesis, have been found in the coronary arteries of infants and children. 1,2 These early lesions are present in the aortas and coronary arteries of many newborn babies and fetuses 3,4 and occur in a distribution similar to that of advanced lesions in adults, 1,3 suggesting a role for the prenatal environment in the pathogenesis of atherosclerosis.Animal models suggest that maternal diet during pregnancy influences susceptibility to atherosclerosis. Rats exposed during gestation to maternal energy-or proteinrestricted diets have an increased incidence of endothelial dysfunction and hypertension. 5-8 Similar outcomes have been observed in the offspring of rats fed a high-fat diet during pregnancy. 9,10 Whether there is any relation in humans between characteristics of maternal diet during pregnancy and atherogenesis is not known, although the observation that maternal hypercholesterolemia during pregnancy is linked with faster progression of early atherosclerotic lesions in children suggests that the type and quantity of fat in the maternal diet may play a role in fetal atherogenesis. 11 High-resolution B-mode ultrasound measurements of carotid intima-media thickness (IMT) are widely used as a marker of early atherosclerosis in adults 12,13 and predict vascular events across a wide age range. 13 Fewer studies have investigated IMT in children, but children who are obese, hypercholesterolemic, or diabetic have an increased IMT. 14 -16 Exposure to cardiovascular risk factors in early life has long-term influences on vascular function, predicting IMT and arterial elas...

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supporting

confidence: 69%

Maternal Diet During Pregnancy and Carotid Intima–Media Thickness in Children

Gale

Jiang

Robinson

et al. 2006

ATVB

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“…Gch1 is a crucial (rate-limiting) component of the tetrahydrobiopterin synthetic pathway and has been directly implicated in diabetes-associated endothelial dysfunction through its critical role in nitric oxide (NO) synthesis (30,31). Interestingly, folate supplementation of protein-restricted dams, known to buffer against changes in DNA methylation (32), prevented the development of hypertension and reduced NO synthesis and endothelial dysfunction that was otherwise observed in male offspring (33,34). We hypothesize that the Gch1 down-regulation we observed with IUGR could play a role in the progressive ␤-cell decline that we have previously observed (9), through direct effects on the ␤-cells or islet vascularization (27).…”

Section: Discussionmentioning

confidence: 99%

Experimental Intrauterine Growth Restriction Induces Alterations in DNA Methylation and Gene Expression in Pancreatic Islets of Rats

Thompson

Fazzari

Niu

et al. 2010

Journal of Biological Chemistry

143

119

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Intrauterine growth restriction (IUGR) increases susceptibility to age-related diseases, including type 2 diabetes (T2DM), and is associated with permanent and progressive changes in gene expression. Our study was designed to test whether epigenomic dysregulation mediates the cellular memory of this intrauterine event. To test this hypothesis, we isolated pancreatic islets from control and IUGR (induced by bilateral uterine artery ligation at day 18 of fetal life) animals at 7 weeks of age. Using the HELP (HpaII tiny fragment enrichment by ligationmediated PCR) assay, we generated the first DNA methylation map at almost 1 million unique sites throughout the rat genome in normal pancreatic islet cells, allowing us to identify the changes that occur as a consequence of IUGR. We validated candidate dysregulated loci with quantitative assays of cytosine methylation and gene expression. IUGR changes cytosine methylation at ϳ1,400 loci (false discovery rate of 4.2%) in male rats at 7 weeks of age, preceding the development of diabetes and thus representing candidate loci for mediating the pathogenesis of metabolic disease that occurs later in life. Epigenetic dysregulation occurred preferentially at conserved intergenic sequences, frequently near genes regulating processes known to be abnormal in IUGR islets, such as vascularization, ␤-cell proliferation, insulin secretion, and cell death, associated with concordant changes in mRNA expression. These results demonstrate that epigenetic dysregulation is a strong candidate for propagating the cellular memory of intrauterine events, causing changes in expression of nearby genes and long term susceptibility to type 2 diabetes.Perturbations in the intrauterine environment resulting in poor fetal growth increase the susceptibility for age-related diseases, particularly type 2 diabetes mellitus (T2DM) 4 and cardiovascular disease (1, 2). Moreover, intrauterine growth restriction (IUGR) can cause permanent and progressive changes in gene expression, affecting important metabolically active tissues such as pancreatic islets (3-6). These changes are often present at birth or during early life, and can precede the development of overt disease in rodents by months and in humans by decades. Although the mechanisms that may mediate the "fetal origin of adult disease" (7) remain unclear, dysregulation of the epigenome could play an important role and may explain the changes in gene expression that are heritably maintained through cell divisions in IUGR animals throughout life (8).We have developed an animal model of IUGR caused by uteroplacental insufficiency, which limits the supply of critical substrates (e.g. nutrients, oxygen, growth factors, and hormones) to the fetus (9). This deficient intrauterine environment affects fetal development through permanent and progressive dysregulation of gene expression and function of susceptible cells (e.g. pancreatic ␤-cells) and leads to the development of T2DM in adulthood (3, 6, 9). In particular, expression of pancreatic and duodenal home...

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“…The translational relevance of our D21 findings is that IUGR males are known to be at a disadvantage compared with IUGR females in many aspects of cardiovascular health especially in early adult life. Male offspring develop vascular dysfunction and hypertension, whereas female offspring seems to be protected (26,27). Literature over the past two decades has shown that IGF-1 not only controls growth properties but also has important effects on carbohydrate, lipid, and protein metabolism (2).…”

Section: Discussionmentioning

confidence: 99%

IUGR prevents IGF-1 upregulation in juvenile male mice by perturbing postnatal IGF-1 chromatin remodeling

Fung

Yang

et al. 2015

Pediatr Res

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Background: Intrauterine growth restriction (IUGR) offspring with rapid catch-up growth are at increased risk for early obesity especially in males. Persistent insulin-like growth factor-1 (IGF-1) reduction is an important risk factor. Using a mouse model of maternal hypertension-induced IUGR, we examined IGF-1 levels, promoter DNA methylation, and histone H3 covalent modifications at birth (D1). We additionally investigated whether prenatal perturbations could reset at preadolescence (D21). Methods: IUGR was induced via maternal thromboxane A 2 -analog infusion in mice. results: IUGR uniformly decreased D1 IGF-1 mRNA and protein levels with reduced promoter 1 (P1) transcription and increased P1 DNA methylation. IUGR males also had increased H3K4ac at exon 5 and 3′ distal UTR. At D21, IUGR males continued to have decreased IGF-1 levels, originating from both P1 and P2 with reduced 1A variant. IUGR males also had decreased activation mark of H3K4me3 at P1 compared with sham males. In contrast, D21 IUGR females normalized their IGF-1 levels, in association with an increased activation mark of H3K4me3 at P1 compared with sham females. conclusion: IUGR uniformly affected D1 hepatic IGF-1 epigenetic modifications in both sexes. However, at preadolescence, IUGR males are unable to correct for the prenatal reduction possibly due to a more perturbed IGF-1 chromatin structure.i ntrauterine growth restriction (IUGR) predisposes offspring toward early-onset metabolic syndrome. This predisposition is particularly pertinent with rapid postnatal catch-up growth and affects males more than females (1). The molecular mechanisms underlying this sex-specific predisposition remain elusive. Insulin-like growth factor 1 (IGF-1), a major regulator of growth and metabolism, has generated significant interest in the field (2). IGF-1 disruption has been implicated in aberrant growth and development of metabolic syndrome in both IUGR humans and animal models (3-6). In particular, decreased IGF-1 have been observed in IUGR humans who ultimately develop metabolic syndrome as adults (7,8).The IGF-1 gene is an ideal candidate to examine IUGR's effects not only because of its growth and metabolic properties but because of its complex gene structure allowing for developmental-and tissue-specific expression. The majority of serum IGF-1 is synthesized from the liver (9). The IGF-1 gene is regulated by two alternative promoters, promoter P1 initiates transcription from exon 1 while promoter P2 from exon 2. P1 is active in fetal life, whereas P2 becomes upregulated at ~3 wk of life when growth hormone exerts its effects on the rodent IGF-1 gene (10). The rodent IGF-1 gene also has an alternatively spliced exon, with the A variant excluding exon 5 and the B variant includes exon 5. Both alternative promoter selection and alternative exon splicing require specific epigenetic modifications to direct transcriptional machinery for specific mRNA transcript generation (11,12).Given that prenatal insults are known to affect gene-specific DNA methylation a...

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Dietary Protein Restriction in Pregnancy Induces Hypertension and Vascular Defects in Rat Male Offspring

Cited by 227 publications

References 66 publications

Maternal Diet During Pregnancy and Carotid Intima–Media Thickness in Children

Maternal Diet During Pregnancy and Carotid Intima–Media Thickness in Children

Experimental Intrauterine Growth Restriction Induces Alterations in DNA Methylation and Gene Expression in Pancreatic Islets of Rats

IUGR prevents IGF-1 upregulation in juvenile male mice by perturbing postnatal IGF-1 chromatin remodeling

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