Folate Supplementation During Pregnancy Improves Offspring Cardiovascular Dysfunction Induced by Protein Restriction

Abstract

Abstract-Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet Ϯ5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (PϽ0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (PϽ0.01), impaired acetylcholine-induced vasodilatation (PϽ0.01), and reduced levels of endothelial NO synthase mRNA (PϽ0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function. Key Words: diet Ⅲ endothelium Ⅲ hypertension, experimental Ⅲ nitric oxide Ⅲ pregnancy C ardiovascular disease arises from complex interactions between genetic susceptibility and adverse environmental influences. Increasing evidence suggests that environmental, particularly nutritional, factors operate from the earliest stages of development. 1,2 The concept of developmental origins of adult disease 3 has been strengthened by observations in animals that an unbalanced diet in pregnancy leads to cardiovascular and metabolic dysfunction in the offspring. 4 The offspring phenotype induced by such dietary manipulation has similarities with the human metabolic syndrome, providing further evidence for a developmental component to the etiology of this syndrome and giving models for investigating the underlying mechanisms. 5 In the rat, we have demonstrated previously that maternal protein restriction during pregnancy leads to impaired endothelial function in the uterine and mesenteric arteries of the dam in late pregnancy 6 and that supplementation of the maternal diet with glycine ...

Fetal programming of CVD and renal disease: animal models and mechanistic considerations

“…Sinclair et al reported that periconceptual depletion of methyl donors in sheep impacted upon methylation of approximately 4 % of the genome in affected lambs (79) . Furthermore, the observation that dietary supplementation with C 1 donors, such as folic acid or glycine, can reverse the phenotypic changes associated with undernutrition in rat pregnancy is consistent with the hypothesis that disturbance of DNA methylation is an important mechanistic driver of programming (80)(81)(82) . The expression of DNA methyltransferases may be modified by the maternal diet and this may explain how undernutrition can alter methylation, gene expression and hence remodel tissues during development (3) .…”

Epigenetic changes in early life and future risk of obesity

“…In some studies, this nutritional constraint is continued during lactation. Offspring from PR dams show a number of features of human cardio-metabolic disease, including hypertension, 34 increased fat deposition and altered feeding behaviour, [35][36][37] impaired glucose homeostasis, dyslipidaemia, 38 vascular dysfunction, 35,39 impaired immunity 40 and increased susceptibility to oxidative stress. 41 The phenotype of the offspring, however, does vary according to the exact composition of the diet.…”

Developmental programming of the metabolic syndrome - critical windows for intervention

“…Several maternal dietary co-factors have also been shown to prevent the development of hypertension in offspring of MLP dams although the mechanisms are not well established. Maternal supplementation with glycine [140,141] , folic acid [142,143] and choline (authors unpublished observations) has been shown to prevent programming-induced elevations in systolic blood pressure in offspring in postnatal life. There is some evidence for an epigenetic basis to these observations utilizing dietary methyl donor and co-factor supplementation; clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring and modify adult health-related phenotypes [107,115] .…”