Maternal Protein Restriction Research Articles

Maternal protein restriction leads to early life alterations in the expression of key molecules involved in the aging process in rat offspring

Recent findings demonstrate that nutrition during the fetal and neonatal periods can affect the life span of an organism. Our previous studies in rodents using a maternal low protein diet have shown that limiting protein and growth during lactation [postnatal low protein (PLP group)] increases longevity, while in utero growth restriction (IUGR) followed by "catch up growth" (recuperated group) shortens life span. The aim of this study was to investigate mechanisms in early postnatal life that could underlie these substantial differences in longevity. At weaning, PLP animals had improved insulin sensitivity as suggested by lower concentrations of insulin required to maintain concentrations of glucose similar to those of the control group and significant upregulation of insulin receptor-beta, IGF-1 receptor, Akt1, Akt2, and Akt phosphorylated at Ser 473 in the kidney. These animals also had significantly increased SIRT1 (mammalian sirtuin) expression. Expression of the antioxidant enzymes catalase, CuZnSOD, and glutathione peroxidase-1 was elevated in these animals. In contrast, recuperated animals had a significantly increased fasting glucose concentration, while insulin levels remained comparable to those of the control group suggesting relative insulin resistance. MnSOD expression was increased in these animals. These data suggest that early nutrition can lead to alterations in insulin sensitivity and antioxidant capacity very early in life, which may influence life span.

Hepatic structural alteration in adult programmed offspring (severe maternal protein restriction) is aggravated by post-weaning high-fat diet

The present study aimed to evaluate the effects of a post-weaning high-fat (HF) diet upon hepatic morphology in rats subjected to perinatal protein restriction. Pregnant Wistar rats were assigned to a normal-protein diet (NP; with 19 % of protein) or a low-protein (LP) diet (with 5 % of protein). At weaning, the following groups were formed: NP and NP-HF, males and females, which were fed standard chow and an HF diet, respectively. Likewise, LP rat dams originated LP and LP-HF offspring, both sexes. Euthanasia was performed at 6 months of age. Three-way ANOVA disclosed a three-factor interaction among sex, perinatal diet and HF diet in relation to body mass, retroperitoneal fat pad, liver mass:tibia length ratio, binucleation rate and hepatocyte area at 6 months old (P < 0.05). The high-fat diet intensified the effects of perinatal protein restriction concerning systolic blood pressure, genital fat pad and hepatocyte number (P < 0.05; two-way ANOVA). Furthermore, higher steatosis rates and insulin and leptin concentrations were found in males fed on the HF diet, indicating a sex-post-weaning diet interaction (P < 0.05; two-way ANOVA). Fetal programming and HF diet as a single stimulus caused mild hypertension at 3 months, an important reduction in hepatocyte number as well as stage 1 steatosis at 6 months. However, hypertension and hepatocyte number deficit were worsened and grade 2 steatosis occurred after exposure to the HF diet. All of these serve to highlight the paramount importance of intra-uterine conditions and postnatal diet quality when it comes to the pathogenesis of chronic diseases.

Maternal low-protein diet during lactation programmes body composition and glucose homeostasis in the adult rat offspring

Previously we have reported that maternal malnutrition during lactation programmes body weight and thyroid function in the adult offspring. In the present study we evaluated the effect of maternal protein restriction during lactation upon body composition and hormones related to glucose homeostasis in adult rats. During lactation, Wistar lactating rats and their pups were divided into two experimental groups: control (fed a normal diet; 23% protein) and protein-restricted (PR; fed a diet containing 8% protein). At weaning, offspring received a normal diet until they were 180 d old. Body weight (BW) and food intake were monitored. Serum, adrenal glands, visceral fat mass (VFM) and carcasses were collected. PR rats showed lower BW (-13%; P < 0.05), VFM (-33%; P < 0.05), total body fat (-33%; P < 0.05), serum glucose (-7%; P < 0.05), serum insulin (-26%, P < 0.05), homeostasis model assessment index (-20%), but higher total adrenal catecholamine content (+90%; P < 0.05) and serum corticosterone concentration (+51%; P < 0.05). No change was observed in food intake, protein mass or total body water. The lower BW of PR rats is due to a reduction of white fat tissue, probably caused by an increase in lipolysis or impairment of lipogenesis; both effects could be related to higher catecholaminergic status, as well as to hypoinsulinaemia. To conclude, changes in key hormones which control intermediary metabolism are programmed by maternal protein restriction during lactation, resulting in BW alterations in adult rats.

Rapid neonatal weight gain in rats results in a renal ubiquinone (CoQ) deficiency associated with premature death

We have recently reported that maternal dietary imbalance during pregnancy and lactation can reduce the lifespan of offspring. Rats that were growth restricted in utero by maternal protein restriction and underwent rapid weight gain when suckled by control fed dams died earlier than animals whose mothers were fed a control diet throughout pregnancy and lactation. We demonstrate here that mitochondrial abnormalities and DNA damage occur in the kidney of offspring who die prematurely. We have established by direct measurement and by in vitro supplementation that mitochondrial abnormalities occur because of a functional deficit of the mitochondrial cofactor coenzyme Q9 (CoQ9). These data provide molecular insight into the association between maternal nutrition and determination of offspring lifespan, and identify, a potential dietary intervention to prevent detrimental consequences of imbalanced maternal nutrition.

Retinoic acid enhances nephron endowment in rats exposed to maternal protein restriction

A reduced nephron complement at birth renders the kidney susceptible to renal disease in adulthood. Retinoic acid (RA; the active metabolite of vitamin A) is linked to nephrogenesis in vitro and in vivo. The aim of this study was to determine the effect of administration of retinoic acid in midgestation in rats on nephron endowment in offspring exposed to maternal protein restriction. Rats were fed either a normal-protein diet (NPD) or a low-protein diet (LPD) during pregnancy and lactation. Half of the dams in the LPD group were injected intraperitoneally with retinoic acid (20 mg/kg) during gestation at embryonic day 11.5. At 4 weeks of age, the offspring were anesthetized and perfusion-fixed, and nephron number estimated using unbiased stereological techniques. Body weight and kidney volume was significantly reduced in all LPD offspring. There was a significant 29% reduction in nephron number in the LPD group compared with the NPD offspring, whereas the number of nephrons in kidneys from the LPD + RA offspring was not significantly different compared with controls. In conclusion, administration of a single bolus dose of retinoic acid during midgestation restored nephron endowment to normal in offspring exposed to maternal protein restriction.

P1-16 Impact on the developmental profile of the murine heart by maternal protein restriction during pregnancy

Aims: We hypothesised that intrauterine environmental factors such as undernutrition may have an impact on cardiac development in prenatal life, leading to cardiac hypertrophy. In this study, we examined the effects of maternal dietary protein restriction (PR) during pregnancy on fetal heart development in the mouse. Study design and Subjects: CD1 mice were placed on control C (18% casein) or protein restricted PR (9% casein) diet during pregnancy. Fetal hearts were collected on day 12 of gestation and the left ventricles (LV) of adult offspring at 6 months. Outcome Measures: p53, e2f1 mRNA expression was measured by real time RT PCR, fetal heart ventricular volumes and surface area of by MRI. Results: No differences were demonstrated in p53 and E2f1 expression in fetal heart or adult LV. MRI revealed smaller hearts in the PR group, both for surface area (PR, 13831±68 vs. C, 16356±37 mm2, p<0.01) and ventricular volume (PR, 22114±43 v C, 27404±10 mm3; p Conclusion: These results indicate that protein restriction during pregnancy leads to a smaller fetal heart (MRI scan), perhaps due to its effect on cell allocation and division. Lack of difference in the expression of p53 and E2f1, genes involved in cell inhibition and apoptosis and cell proliferation, respectively in either group suggest that changes in fetal heart size are due to the reduction of cardiomyocyte growth (supported by lower cyclin g1 expression previously described) in the PR group.

P1-4 Intergenerational programming of blood pressure in rats following maternal protein restriction during pregnancy

Hypothesis: Feeding a low protein diet during rat gestation will programme raised systolic blood pressure in several successive generations. Outcome: The feeding of a low protein diet throughout rat gestation promoted a significant elevation of blood pressure in the resulting offspring. Elevations of blood pressure were transmitted to a subsequent generation via both the maternal and paternal lines. The effect of the low protein diet was lost by the third generation. It is therefore concluded that fetal protein restriction plays a critical role in determining blood pressure and overall disease risk in subsequent generations. This process must involve heritable changes to both male and female gametes. Introduction

P1-67 Plasma and tissue glucocorticoid components are not altered by maternal protein restriction in neonatal or juvenile microswine offspring

P1-67 Plasma and tissue glucocorticoid components are not altered by maternal protein restriction in neonatal or juvenile microswine offspring

P2-141 IUGR accompanied with transcriptional suppression of Igf2 caused by maternal protein restriction during late gestation: a possible link between fetal programming and epigenetics

P2-141 IUGR accompanied with transcriptional suppression of Igf2 caused by maternal protein restriction during late gestation: a possible link between fetal programming and epigenetics

P1-5 Intergenerational programming of a lean phenotype in rats, following maternal protein restriction during pregnancy

Novel, highly selective and potent thrombin inhibitors were identified as a result of combing the 3-benzylsulfonylamino-2-pyridinone acetamide P2–P3 surrogate with weakly basic partially saturated heterobicyclic P1-arginine mimetics 1–8. The design, synthesis, biological activity, and the binding modes of non-covalent thrombin inhibitors featuring P1-4,5,6,7-tetrahydroindazole, 5,6,7,8-tetrahydroquinazoline, and 4,5,6,7-tetrahydrobenzothiazole moieties are described.

P1-17 Maternal protein restriction in microswine: food restriction from weaning to prevent excess intake corrects vascular dysfunction in juvenile offspring

In the present study, we evaluated the effect of largazole (LAR), a marine-derived class I HDAC inhibitor, on tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and matrix metalloproteinase-2 (MMP-2) activity. LAR (1–5 μM) had no adverse effect on the viability of RA synovial fibroblasts. Among the different class I HDACs screened, LAR (0.5–5 μM) inhibited the constitutive expression of HDAC1 (0–30%). Surprisingly, LAR increased class II HDAC [HDAC6] by ~ 220% with a concomitant decrease in HDAC5 [30–58%] expression in RA synovial fibroblasts. SAHA (5 μM), a pan-HDAC inhibitor, also induced HDAC6 expression in RA synovial fibroblasts. Pretreatment of RA synovial fibroblasts with LAR further enhanced TNF-α-induced ICAM-1 and VCAM-1 expression. However, LAR inhibited TNF-α-induced MMP-2 activity in RA synovial fibroblasts by 35% when compared to the TNF-α-treated group. Further, the addition of HDAC6 specific inhibitor Tubastatin A with LAR suppressed TNF-α + LAR-induced ICAM-1 and VCAM-1 expression and completely blocked MMP-2 activity, suggesting a role of HDAC6 in LAR-induced ICAM-1 and VCAM-1 expression. LAR also enhanced TNF-α-induced phospho-p38 and phospho-AKT expression, but inhibited the expression of phospho-JNK and nuclear translocation of NF-κBp65 in RA synovial fibroblasts. These results suggest that LAR activates p38 and Akt pathways and influences class II HDACs, in particular HDAC6, to enhance some of the detrimental effects of TNF-α in RA synovial fibroblasts. Understanding the exact role of different HDAC isoenzymes in RA pathogenesis is extremely important in order to develop highly effective HDAC inhibitors for the treatment of RA.

Protein restriction in lactation confers nephroprotective effects in the male rat and is associated with increased antioxidant expression

Telomere shortening has been implicated in the aging process and various age-associated disorders, including renal disease. Moreover, oxidative stress has been identified as an initiator of accelerated telomere shortening. We have shown previously that maternal protein restriction during lactation leads to reduced renal telomere shortening, reduced albuminuria, and increased longevity in rats. Here we address the hypothesis that maternal protein restriction during lactation is nephroprotective and associated with increased expression of antioxidative enzymes and decreased age-dependent renal telomere shortening. Newborn rats were suckled by a dam fed either a control (20% protein) or low-protein (8% protein) diet. All animals were weaned onto standard chow. Offspring that had been suckled by protein-restricted mothers had reduced albuminuria, N-acetyl-glucosaminidase, and urinary aldosterone excretion. These animals also did not show significant age-dependent renal telomere shortening and hence had significantly longer telomeres at 12 mo of age. This lack of renal telomere shortening was associated with increased levels of the antioxidant enzymes manganese superoxide dismutase, glutathione peroxidase, and glutathione reductase. These findings suggest that beneficial effects of slow growth during lactation are associated with increased antioxidant capacity and prevention of age-dependent telomere shortening in the kidney.

Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations

Epidemiological studies and experimental models show that maternal nutritional constraint during pregnancy alters the metabolic phenotype of the offspring and that this can be passed to subsequent generations. In the rat, induction of an altered metabolic phenotype in the liver of the F1 generation by feeding a protein-restricted diet (PRD) during pregnancy involves the altered methylation of specific gene promoters. We therefore investigated whether the altered methylation of PPARalpha and glucocorticoid receptor (GR) promoters was passed to the F2 generation. Females rats (F0) were fed a reference diet (180 g/kg protein) or PRD (90 g/kg protein) throughout gestation, and AIN-76A during lactation. The F1 offspring were weaned onto AIN-76A. F1 females were mated and fed AIN-76A throughout pregnancy and lactation. F1 and F2 males were killed on postnatal day 80. Hepatic PPARalpha and GR promoter methylation was significantly (P<0 x 05) lower in the PRD group in the F1 (PPARalpha 8 %, GR 10 %) and F2 (PPARalpha 11 %, GR 8 %) generations. There were trends (P<0 x 1) towards a higher expression of PPARalpha, GR, acyl-CoA oxidase and phosphoenolpyruvate carboxykinase (PEPCK) in the F1 and F2 males, although this was significant only for PEPCK. These data show for the first time that the altered methylation of gene promoters induced in the F1 generation by maternal protein restriction during pregnancy is transmitted to the F2 generation. This may represent a mechanism for the transmission of induced phenotypes between generations

Fetal Programming of Adult Kidney Disease

The role of the kidney in the pathogenesis of hypertension has long been established, although recent studies challenge renal hegemony and suggest an important role for vascular cells as well (1,2). In recent years, the formulation has expanded and now includes the concept that chronic hypertension and kidney disease are also related to events that occur during the prenatal period and usually result in low birth weight (LBW). A recent overview considered the role of fetal programming in the development of adult kidney disease and hypertension (3). The aim of this review is to present further evidence to support an association between LBW and the increased prevalence of hypertension as well as progression toward chronic kidney disease (CKD) in adult life. Various potential mechanisms for this association are discussed, specifically the low nephron number (LNN) hypothesis and related cellular and molecular mechanisms that have been proposed. LBW infants are defined as infants who weigh ≤2500 g at birth. Infants who are delivered before 37 wk from the first day of the last menstrual period are termed preterm. The LBW infant population can be divided into preterm, appropriate for gestational age (AGA), or small for gestational age (SGA). The predominant cause of LBW infants in the United States is preterm birth, whereas in developing countries, the cause is often intrauterine growth restriction (IUGR). During the year 2004, 8.1% of births in the United States were LBW, and more than half of these were preterm. During the past two decades, there has been an increase in the prevalence of LBW as higher risk pregnancies progress to term and postnatal survival improves (4) (Figure 1). Figure 1. Percentage of infants who were born preterm and percentage who were born with low birth weight (LBW; defined in text): United States, 1990, 1995, 2000, …

Gut growth and glucose tolerance in newborn pigs subjected to prenatal protein restriction and postnatal Glucagon-like Peptides

Abstract Fetal protein restriction is potentially associated with organ dysfunctions after birth (e.g. impaired gut growth, glucose tolerance and pancreatic β-cell function). Just after birth, gut growth and maturation is stimulated by enteral food intake, and inhibited by total parenteral nutrition (TPN), in part mediated via differential release of insulino- and intestino-tropic hormones like the Glucagon-Like Peptides 1 and 2 (GLP-1, GLP-2). We hypothesized that short-term co-infusion of GLP-1 and GLP-2 would stimulate pancreatic and intestinal growth in newborn TPN-fed pigs subjected to prenatal protein restriction. Two sows were fed a protein-restricted diet (PR: 8% crude protein during last 50% of gestation) while a third sow was fed a control diet (C: 15% crude protein). PR pigs were killed either at birth ( n = 7) or after 3 days TPN with ( n = 6) or without ( n = 4) intravenous infusion of a mixture of synthetic human GLP-1 7–37 and GLP-2 1–33 (each 50 μg/kg/d). At birth, PR piglets did not show reduced body weight, relative to controls (1.45 vs. 1.50 kg), but significantly reduced weight of the small intestine (18.0 ± 0.6 vs. 21.9 ± 0.5 g/kg, P P = 0.10). Co-infusion GLP-1 and GLP-2 into PR pigs resulted in increased basal glucose levels (5.3 vs. 4.0 mM), and glucose-stimulated insulin release, but did not have any significant effect on body weight, or weight of internal organs (heart, lungs, spleen, kidneys, adrenals, stomach, colon, liver, intestine, pancreas). We conclude that short-term (3 days) infusion of native GLP-1 and GLP-2 does not stimulate gut growth or glucose tolerance in TPN-fed piglets born from protein-restricted mothers. Moderate maternal protein restriction does however cause significant reduction in intestinal growth in newborn piglets which may decrease the neonatal digestive capacity.

Effects of dietary protein restriction on nephron number in the mouse

In rats, maternal protein restriction reduces nephron endowment and often leads to adult hypertension. Sex differences in these responses have been identified. The molecular and genetic bases of these phenomena can best be identified in a mouse model, but effects of maternal protein restriction on kidney development have not been examined in mice. Therefore, we determined how combined prenatal and postnatal protein restriction in mice affects organ weight, glomerular number and dimensions, and renal expression of angiotensin receptor mRNA, in both male and female offspring. C57/BL6/129sv mice received either a normal (20% wt/wt; NP) or low (9% wt/wt; LP) protein diet during gestation and postnatal life. Offspring were examined at postnatal day 30. Protein restriction retarded growth of the kidney, liver, spleen, heart, and brain. All organs except the brain weighed less in female than male offspring. Protein restriction increased normalized (to body weight) brain weight, with females having relatively heavier brains than males. The effects of protein restriction were not sex dependent, except that normalized liver weight was reduced in males but increased in females. Glomerular volume, but not number, was greater in female than in male mice. Maternal protein restriction reduced nephron endowment similarly in male and female mice. Renal expression of AT(1A) receptor mRNA was approximately sixfold greater in female than male NP mice, but similar in male LP and female LP mice. We conclude that maternal protein restriction reduces nephron endowment in mice. This effect provides a basis for future studies of developmental programming in the mouse.

Maternal protein restriction permanently programs adipocyte growth and development in adult male rat offspring

We previously demonstrated that maternal protein restriction (MPR) during pregnancy and lactation led to fetal growth restriction and development of increased visceral adiposity in adult male rat offspring. Here we studied the rate of proliferation and differentiation of adipocyte precursors (preadipocytes) in vitro to investigate whether MPR may permanently program adipocyte growth and development in adult male offspring. Preadipocytes were isolated from visceral adipose tissue of control and MPR offspring at 130 days of age, and cultured under standard conditions. The rate of proliferation was studied by [(3)H]-thymidine incorporation, and the rate of differentiation assessed with the use of biochemical and morphological markers. Although it did not affect the rate of differentiation, MPR increased the rate of preadipocyte proliferation by almost twofold. To ascertain if the increased proliferation was due to persisting in vivo influences or aberrations inherent in the precursor cells, we studied the rate of preadipocyte proliferation in subcultures. We found that the increased rate of proliferation of MPR preadipocytes persisted throughout the first two subcultures, indicative of an inherent abnormality. In addition, we examined the rate of preadipocyte proliferation under reduced serum conditions. We showed that MPR reduced the rate of preadipocyte proliferation to 56 and 35% of the control in the presence of 5 and 2.5% serum, respectively. Taken together, these results demonstrate that MPR permanently programs adipocyte growth and development such that adipocyte precursors derived from MPR offspring replicate excessively under standard culture conditions but exhibit markedly attenuated growth rate under reduced serum conditions.

Suckling a protein-restricted rat dam leads to diminished albuminuria in her male offspring in adult life: a longitudinal study

BackgroundPrevious studies have shown that in male rats, exposure to maternal protein restriction either in utero or whilst suckling can have profound effects on both longevity and kidney telomere lengths. This study monitored albuminuria longitudinally in male rats whose mothers had been protein restricted either during pregnancy or lactation.MethodsPregnant Wistar rats were fed either a 20% ('control') or an 8% protein ('low protein') diet. At two days of age some of the pups were cross-fostered to dams fed the diet that was not given to their biological mothers. At weaning all pups were fed standard chow. Urine samples were collected for the measurement of albumin and creatinine at monthly intervals from two months-of-age. Longitudinal analysis was then performed using repeated measures analysis of variance.ResultsOverall estimated marginal geometric mean (95 % confidence interval) urine albumin to creatinine ratios were: control animals 79.5 (57.2~110.6) g/mol (n = 6 litters, 24 animals in total), those exposed in utero to maternal protein restriction 71.0 (47.4~106.5) (n = 4 litters, 16 animals in total), those exposed to maternal protein restriction whilst suckling 21.2 (14.7~30.4) (n = 5 litters, 20 animals in total) (p < 0.001). These latter animals had lower albumin to creatinine ratios than either of the two other groups (both p < 0.001), which had ratios that were indistinguishable from each other (p = 1.0). Similar results were gained using 24 h. urine albumin excretion rates. These differences became evident from three months-of-age and were long-lasting.ConclusionAnimals exposed to maternal protein restriction whilst suckling exhibited lower urine albumin excretions during much of adult life. As urine albumin can be nephrotoxic, these rats therefore appeared to be relatively protected against future nephron damage like that previously observed in animals exposed to maternal protein restriction in utero.

Comment on: Nyirenda MJ, Dean S, Lyons V, Chapman KE, Seckl JR (2006) Prenatal programming of hepatocyte nuclear factor 4a in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’? Diabetologia 49: 1412–1420, and on: McCurdy CE, Friedman JE (2006) Early foetal programming of hepatic gluconeogenesis: glucocorticoids strike back. Diabetologia 49:1138–1141

Nyirenda et al. present compelling new evidence on the mechanism of fetal programming of gluconeogenesis by glucocorticoid administration during the last third of pregnancy in rats [1], a study that is commented on by McCurdy and Friedman [2]. Nyirenda et al. focus on a fluxgenerating enzyme of gluconeogenesis (phosphoenolpyruvate carboxykinase [PCK]) and the factors involved in its transcription, showing how PCK mRNA and that of its controlling transcription factors are localised within the hepatic acinus. However, this picture is incomplete. It is known that under normal conditions gluconeogenesis is mainly periportal, and about 24% of the new glucose formed is re-taken up in the perivenous cells, which are rich in the enzyme glucokinase. In the adult offspring of rat dams subjected to restricted protein intake during pregnancy and lactation, the perivenous uptake of glucose is much decreased, and the activity of total glucokinase (both free and bound to glucokinase regulatory protein in the nucleus) is greatly reduced [3, 4], leading eventually to glucose intolerance–a possible model of type 2 diabetes in man. Glucokinase transcription, however, is unchanged in these programmed offspring, suggesting an effect on nucleo-cytoplasmic transport of glucokinase, which resides in the nucleus in the starved state but translocates to the cytosol postprandially. The difficulty in attributing control of gluconeogenesis to transcriptional events is that they are too slow [4] to provide the rapid switch-off of hepatic glucose output and the hepatic storage of glucose as glycogen seen in the postprandial state. A further effect of rats fetally programmed by maternal protein restriction is that the hepatic acini are enlarged to about twice the normal volume. Large lobules are also seen in pregnancy and in regenerating liver after partial hepatectomy in the rat [5, 6]. The consequences of this enlargement are unknown but it would be of interest to determine whether the same enlargement occurs in animals fetally programmed by glucocorticoids.

Maternal undernutrition reduces aortic wall thickness and elastin content in offspring rats without altering endothelial function

Epidemiological studies suggest a link between fetal/early infant nutrition and adult coronary artery disease. In the present study, we examined the effects of altering nutrition during gestation, lactation and juvenile life on aortic structure and function in rats. Wistar rat dams were fed either a control or low-protein diet throughout pregnancy, or a low-protein diet for the final 7 days of gestation only. At 21 days post-partum, male pups were weaned on to a control, low-protein or high-fat diet. At 12 weeks, the offspring rats were killed. In 46 rats, aortic sections were mounted and stained to assess media thickness and elastin content. In a further 38 rats, aortic rings were suspended in an organ bath and vascular reactivity was tested with dose-response curves to the endothelium-dependent dilator acetylcholine and the endothelium-independent dilator sodium nitroprusside. Rats exposed to maternal protein restriction while in utero had a significantly decreased aortic wall thickness compared with control rats (P=0.005). Total elastin content of the aorta was also decreased by both maternal low-protein (P=0.02) and early postnatal low-protein (P=0.01) diets. Neither maternal nor postnatal low-protein or high-fat diets, however, resulted in any significant changes in arterial dilator function. In conclusion, fetal undernutrition in rats, induced via a maternal low-protein diet, causes a decrease in aortic wall thickness and elastin content without altering aortic dilator function. These changes in vascular structure may amplify aging-related changes to the vasculature and contribute to the pathophysiology of the putative link between impaired fetal growth and adult cardiovascular disease.