Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep

Abstract

-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...

Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep

“…pregnancy; nutrition; fetus; epigenetic IT HAS BEEN DEMONSTRATED in a range of epidemiological and experimental studies that exposure of the oocyte, embryo, or fetus to a range of environmental stressors, including poor maternal nutrition, results in poor metabolic and cardiovascular outcomes in postnatal life (8,9,13,22,25,41,42,53,56). In sheep, maternal undernutrition from 60 days before to 30 days after conception resulted in an impairment of the insulin and glucose responses to a glucose tolerance test at 10 mo after birth (49).…”

Periconceptional Undernutrition of Ewes Impairs Glucose Tolerance in Their Adult Offspring

“…Fetuses of ewes undernourished (UN) before until 7 d after mating also showed altered development of the HPA axis (21) and altered fetoplacental growth (22). Late gestation twin fetuses of ewes UN only during the preattachment period (days 0 -7) had altered regulation of blood pressure (23). We have shown that maternal undernutrition from 61 d before until 30 d after mating resulted in extensive changes in the late gestation fetus, including altered regulation of fetal growth (6,24) and the fetal somatotrophic axis (25), changes in placental function, and accelerated maturation of the HPA axis (26) resulting in preterm birth (27).…”

Adverse prenatal environment and kidney development: implications for programing of adult disease

“…The data are primarily derived from either rodent (see Watkins et al (2008aWatkins et al ( ,b, 2010) or sheep models (Edwards & McMillen (2002), , 2010, Todd et al 2009, Lie et al 2013, Nicholas et al 2013. As shown in the Table 1, the timing of the periconceptional insult may include oocyte maturation and the preimplantation period.…”

“…Using a maternal diet containing 70% of required energy from 6 weeks before mating until day 7 of pregnancy, late gestation twin fetuses had increased blood pressure (Edwards & McMillen 2002). Kidneys of undernourished fetuses were of a similar weight to control at day 50 of pregnancy, though they exhibited increased expression of renal IGF1 and HSD11B2 mRNA but decreased IGF1R mRNA expression , suggesting that renal development may be affected.…”