A series of epidemiological studies have described a relationship between low birth weight and high blood pressure in adult life and have proposed that factors associated with restriction of growth in utero act to reprogramme the development of the cardiovascular system which leads to the emergence of hypertension in adult life (Barker et al. 1990; Barker, 1992). It has also been demonstrated in pregnant rats that maternal protein restriction results in high blood pressure in the growth restricted offspring (Langley & Jackson, 1994). Interestingly, in these experiments treatment of the offspring for a 3 week period with the angiotensin converting enzyme (ACE) inhibitor captopril normalized the blood pressure (Langley-Evans & Jackson, 1995). These studies in the postnatal rat provide clear evidence that the renin-angiotensin system is important in the maintenance of hypertension in the offspring after maternal nutrient restriction during pregnancy. It is unknown, however, whether growth restriction in utero is associated with changes in the role of the renin-angiotensin system in the regulation of arterial blood pressure before birth. A model of experimental restriction of placental growth and function which results in fetal hypoxaemia, hypoglycaemia and growth restriction has been previously described (Robinson et al. 1979(Robinson et al. , 1980).In the present study we have also investigated the effects of experimental restriction of placental growth and function, and hence fetal growth, on fetal arterial blood pressure during late gestation and we have infused captopril to determine the role of the endogenous renin-angiotensin system in the maintenance of blood pressure in the growth restricted fetus. We have also investigated the effects of placental restriction on the blood pressure responses of the growth restricted fetus to increasing doses of angiotensin II (AII). METHODS Animals and surgeryAll procedures were approved by The University of Adelaide Animal Ethics Committee. Thirty-three pregnant Border ² Leicester cross Merino ewes were used in this study. In 14 ewes (placental restriction group; PR), the majority of endometrial caruncles were removed from the uterus prior to conception as previously described (Robinson et al. 1979). This procedure restricts the number of placental cotyledons which are formed subsequently limiting placental and hence fetal growth (Robinson et al. 1979). All surgery was performed under aseptic conditions with general anaesthesia induced by an intravenous injection of sodium thiopentone (1•25 g ml¢, Boehringer Ingelheim, NSW, Australia) and

Evidence from epidemiologic, clinical, and experimental studies has shown that a suboptimal intrauterine environment during early pregnancy can alter fetal growth and gestation length and is associated with an increased prevalence of adult hypertension and cardiovascular disease. It has been postulated that maternal nutrient restriction may act to reprogram the development of the pituitary-adrenal axis, resulting in excess glucocorticoid exposure and adverse health outcomes in later life. It is unknown, however, whether maternal nutrient restriction during the periconceptional period alters the development of the fetal pituitary-adrenal axis or whether the effects of periconceptional undernutrition can be reversed by the provision of an adequate level of maternal nutrition throughout the remainder of pregnancy. We have investigated the effect of restricted periconceptional nutrition (70% of control feed allowance) from 60 days before until 7 days after mating and the effect of restricted gestational nutrition from Day 8 to 147 of gestation on the development of the fetal hypothalamo-pituitary adrenal (HPA) axis in the sheep. In these studies, we have also investigated the effects of fetal number and sex on the pituitary-adrenal responses to periconceptional and gestational undernutrition. In ewes maintained on a control diet throughout the periconceptional and gestational periods, fetal plasma ACTH concentrations were higher and the prepartum surge in cortisol occurred earlier in singletons compared with twins. Plasma ACTH concentrations were also significantly higher in male compared with female singletons, and in twin fetuses, the prepartum surge in cortisol concentrations occurred earlier in males than in females. Periconceptional undernutrition resulted in higher fetal plasma concentrations of ACTH between 110 and 145 days of gestation and a significantly greater cortisol response to a bolus dose of corticotropin-releasing hormone in twin, but not singleton, fetuses in late gestation. We have therefore demonstrated that fetal number and sex each has an impact on the timing of the prepartum activation of the HPA axis in the sheep. Restriction of the level of maternal nutrition before and in the first week of a twin pregnancy results in stimulation of the fetal pituitary-adrenal axis in late gestation, and this effect is not reversed by the provision of a maintenance control diet from the second week of pregnancy.

1. We have investigated the effect of a 50 % reduction in maternal nutrient intake during the last 30 days of pregnancy on arterial blood pressure and on arterial blood pressure responses to angiotensin II (AII) and the angiotensin converting enzyme (ACE) inhibitor captopril in the sheep fetus at 115-125 and at 135-145 days gestation (term = 147 ± 3 days gestation).2. Fetal plasma glucose concentrations were lower in the undernourished (UN) group compared to the control animals. There was no difference, however, in fetal plasma cortisol or adrenocorticotrophic hormone (ACTH) concentrations between the UN and control groups between 115 and 145 days gestation.3. During the first 10 days of undernutrition, maternal plasma concentrations of cortisol were increased in the UN group compared to controls. At 115-125 days gestation, fetal arterial blood pressure was also higher in the UN group compared with controls and there was an inverse relationship (r = _0.62, P < 0.05) between mean arterial pressure and the fetal plasma concentrations of ACTH in the UN group. Fetal blood pressure responses to increasing doses of angiotensin II were also higher (P < 0.05) in UN compared to control animals at 115-125 days gestation.4. Between 135 and 145 days gestation, fetal arterial blood pressure was increased in UN fetal sheep and mean arterial blood pressure was correlated with fetal plasma concentrations of cortisol.5. Increased arterial blood pressure and responsiveness to AII measured in the fetuses of nutrient-restricted ewes may be related in part to fetal exposure to the actions of cortisol derived from transplacental transfer during the first 10 days after the start of the restricted feeding regime.

A series of epidemiological, clinical and experimental studies have shown that there are associations between the fetal and neonatal nutritional environment and the amount and distribution of adipose tissue in adult life. This review considers the evidence for these relationships and discusses the potential impact of the prenatal nutritional experience on the development of the endocrine and neuroendocrine systems that regulate energy balance, with a particular emphasis on the role of the adipocyte-derived hormone, leptin. In the rodent, leptin derived from the mother may exert an important influence on the development of the appetite regulatory neural network and on the subsequent regulation of leptin synthesis and the risk for obesity in the offspring. In species such as the human and sheep, there is also recent evidence that the synthesis and secretion of adipocyte-derived hormones, such as leptin, are regulated in fetal life. Furthermore, the hypothalamic neuropeptides that regulate energy intake and expenditure in adult life are also present within the fetal brain and may be regulated by the prevailing level of maternal and hence fetal nutrient and hormonal signals, including leptin. This work is important in determining those initiating mechanisms within the 'fat -brain' axis in early life that precede the development of adult obesity.

-It has been proposed that fetal adaptations to intrauterine nutrient deprivation permanently reprogram the cardiovascular system. We investigated the impact of restricted periconceptional nutrition and/or restricted gestational nutrition on fetal arterial blood pressure (BP), heart rate, rate pressure product, and the fetal BP responses to ANG II and the angiotensin-converting enzyme inhibitor captopril during late gestation. Restricted periconceptional nutrition resulted in an increase in fetal mean arterial BP between 115 and 125 days gestation (restricted 41.5 Ϯ 2.8 mmHg, n ϭ 12; control 38.5 Ϯ 1.5 mmHg, n ϭ 13) and between 135 and 147 days gestation (restricted 50.5 Ϯ 2.2 mmHg, n ϭ 8; control 42.5 Ϯ 1.9 mmHg, n ϭ 10) as well as an increase in the rate pressure product in twin, but not singleton, fetuses between 115 and 147 days gestation. Mean BP and fetal plasma ACTH were also positively correlated in twin, but not singleton, fetuses. This is the first demonstration that maternal undernutrition during the periconceptional period results in an increase in fetal arterial BP. This increase occurs concomitantly with an increase in fetal ACTH but is not dependent on activation of the fetal renin-angiotensin system. fetus; blood pressure; renin-angiotensin system A WORLD-WIDE SERIES of epidemiological studies has demonstrated associations between low birth weight and poor adult health outcomes, including raised arterial blood pressure (BP) and coronary heart disease (1-3). The reproducibility of these associations across many populations has generated the "fetal origins of adult disease hypothesis." This hypothesis states that fetal adaptations to a period of intrauterine nutrient deprivation result in a permanent reprogramming of the developmental pattern of key organ systems and in subsequent pathological consequences in adult life (3,22). Recent data from the Dutch "Winter Hunger" Famine study provided evidence that the timing of fetal nutrient restriction in pregnancy is important in determining specific pathophysiological outcomes (30,32,33). Individuals exposed to famine in the first trimester only, when the nutrient demands of the conceptus are minimal, had an increased prevalence of coronary heart disease compared with individuals not exposed to the famine during this period (30,32,33). Although adult hypertension was not specifically associated with exposure to maternal malnutrition during any one trimester, it was associated with any level of maternal undernutrition that resulted in reduced fetal growth (33). In experimental studies, rats born to mothers fed a low-protein diet either during the preimplantation period or during mid or late gestation also developed high BP in later life (17,20). It has been proposed that maternal undernutrition may result in exposure of the embryo or fetus to excess glucocorticoids and that this exposure permanently changes the program of structural or functional development of the cardiovascular system (6,18,19,21,35). We previously showed in the sheep that maternal und...