Marie-Amélie Lukaszewski

Nutritional manipulations in the perinatal period program adipose tissue in offspring

Epidemiological studies demonstrated initially that maternal undernutrition results in low birth weight with increased risk for long-lasting energy balance disorders. Maternal obesity and diabetes associated with high birth weight, excessive nutrition in neonates, and rapid catchup growth also increase the risk of adult-onset obesity. As stated by the Developmental Origin of Health and Disease concept, nutrient supply perturbations in the fetus or neonate result in long-term programming of individual body weight set point. Adipose tissue is a key fuel storage unit involved mainly in the maintenance of energy homeostasis. Studies in numerous animal models have demonstrated that the adipose tissue is the focus of developmental programming events in a sex- and depot-specific manner. In rodents, adipose tissue development is particularly active during the perinatal period, especially during the last week of gestation and during early postnatal life. In contrast to rodents, this process essentially takes place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several mechanisms of adipose tissue programming. Offspring from malnourished dams present adipose tissue with a series of alterations: impaired glucose uptake, insulin and leptin resistance, low-grade inflammation, modified sympathetic activity with reduced noradrenergic innervations, and thermogenesis. These modifications reprogram adipose tissue metabolism by changing fat distribution and composition and by enhancing adipogenesis, predisposing the offspring to fat accumulation. Subtle adipose tissue circadian rhythm changes are also observed. Inappropriate hormone levels, modified tissue sensitivity (especially glucocorticoid system), and epigenetic mechanisms are key factors for adipose tissue programming during the perinatal period.

Preterm Birth and Hypertension Risk: The Oxidative Stress Paradigm

The majority of epidemiological studies in developmental programming have explored the influence of low birth weight (irrespective of gestational age) on long-term chronic disease in individuals born during the first half of the 20th century.1,2 Low birth weight neonates may represent infants born at term with intrauterine growth restriction (IUGR) or born preterm with or without IUGR. As such, there is emerging interest in the effects of preterm birth alone (beyond birth weight and IUGR) on specific aspects of human development and long-term health. Approximately 10% of all births worldwide are preterm (before 37 completed weeks of gestation).3 Besides being of low birth weight, preterm neonates are suddenly and prematurely exposed to the extrauterine environment at a time when organogenesis is incomplete. Exposure postnatally to factors such as high oxygen concentrations,4 medications5 (including glucocorticoids),6 and inadequate nutrition7 likely adversely influence postnatal growth and ongoing organ development. In addition to possible genetic and epigenetic factors that may contribute to hypertension risk (including hypertension-related complications of pregnancy), a multitude of aspects related to both intrauterine and extrauterine growth, as well as the postnatal environment, may all play an important role in the programming of hypertension in individuals born preterm. In this review, we will highlight, in particular, the potential effect of oxidative stress associated with preterm birth on neonatal development and future disease risk. The survival of neonates born at low and very low gestational ages is recent in the history of medicine and has increased remarkably over the last few decades. The first generations of survivors of very preterm birth are currently just reaching adulthood and as such are providing emerging evidence of chronic health conditions, such as hypertension. The link between preterm birth and hypertension risk (independent of birth weight) has been …

Perinatal nutrition programs the hypothalamic melanocortin system in offspring.

Epidemiological studies initially suggested that maternal undernutrition leading to low birth weight may predispose for long-lasting energy balance disorders. High birth weight due to maternal obesity or diabetes, inappropriate early postnatal nutrition, and rapid catch-up growth, may also sensitize to increased risk of obesity. As stated by the Developmental Origin of Health and Disease concept, the perinatal perturbation of fetus/neonate nutrient supply might be a crucial determinant of individual programming of body weight set-point. The hypothalamic melanocortin system composed of the melanocortin receptor 4, its agonist α-melanin-stimulating hormone (α-MSH), and its antagonist agouti-related protein (AgRP) is considered as the main central anorexigenic pathway controlling energy homeostasis. Studies in numerous animal models demonstrated that this system is a prime target of developmental programming by maternal nutritional manipulation. In rodents, the perinatal period of life corresponds largely to the period of brain maturation (i. e., melanocortin neuronal differentiation and development of their neural projections). In contrast, these phenomena essentially take place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several common offspring programming mechanisms. Offspring from malnourished dams present a hypothalamic melanocortin system with a series of alterations: impaired neurogenesis and neuronal functionality, disorganization of feeding pathways, modified glucose sensing, and leptin/insulin resistance. Overall, these alterations may account for the long-lasting dysregulation of energy balance and obesity. Following maternal malnutrition, hormonal and epigenetic mechanisms might be responsible for melanocortin system programming in offspring.

PS 13-03 TRANSIENT NEONATAL HIGH OXYGEN EXPOSURE ACCELERATES ADULT CARDIAC BASELINE AND ANG II-INDUCED PROOXIDATIVE AND PROINFLAMMATORY RESPONSES

Objective : Preterm birth is associated with disequilibrated early life oxidant-antioxidant and proinflammatory conditions that can be carried into adulthood and contribute to the development of organ dysfunction. Neonatally high O2-exposed rats, a model of prematurity-related prooxidative conditions, exhibit adult hypertension, early cardiac dysfunction and fibrosis, and premature angiotensin (ANG) II-induced heart failure. We hypothesized that neonatal high O2 exposure will exaggerate baseline and ANG II-induced cardiac prooxidative and proinflammatory gene expression in adult rats. Design and Method: Sprague-Dawley pups were kept in 80% O2 (H group) or room air (NNI group) from day 3–10 of life. Twelve-weeks-old H and NNI rats were infused with ANG II (100 ng.kg-1.min-1) or saline (NaCl) for 4 weeks (n = 4 per group). RNA extracted from hearts was used in arrays to assess expression of oxidative stress and inflammatory genes. Data is expressed as fold change (F.C.) compared to control NNI+NaCl. Results : H+NaCl exhibited increased baseline Cd68 expression (F.C: 1.47; P < 0.05 vs control), tendancy of increased Nfkb1 and Tnf expression (1.52 and 1.48), and a tendancy of decreased Il1b and Il18 expression (0.72 and 0.78). H+ANGII versus NNI+ANGII exhibited similar increase in Tnf (2.12 vs 2.13; P < 0.05 vs control), greater increase in Cd14, Cd68, and Nfkb1 (2.5 vs 1.78, 2.13 vs 1.94, 2.0 vs 1.7; P < 0.05 vs controls), and a greater tendancy of increase in Tgfb1, Myd88, Cybb, and Gstp1 (2.68 vs 1.82, 2.37 vs 1.31, 1.91 vs 0.98, 2.45 vs 1.61) expression. NNI+ANGII versus H+ANGII exhibited greater increase in expression of genes involved in early inflammatory process, including Ccl2, Icam1, and Vcam1 (2.07 vs 1.56, 1.88 vs 1.36, 2.34 vs 1.29; P < 0.05 vs control). Conclusions : Neonatal high O2 exposure accelerates baseline and ANG II-induced cardiac prooxidative and proinflammatory responses in adult rats, which could account for early cardiac abnormalities and premature ANG II-induced heart failure in this model.

Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn Rats

Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin–angiotensin system. Cardiac renin–angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin–angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague–Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3–P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-&bgr;/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin–angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions.Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin–angiotensin system. Cardiac renin–angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin–angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague–Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3–P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin–angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions. # Novelty and Significance {#article-title-40}

Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn RatsNovelty and Significance

Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin–angiotensin system. Cardiac renin–angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin–angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague–Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3–P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-&bgr;/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin–angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions.Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin–angiotensin system. Cardiac renin–angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin–angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague–Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3–P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin–angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions. # Novelty and Significance {#article-title-40}

Activation of the Cardiac Renin–Angiotensin System in High Oxygen-Exposed Newborn RatsNovelty and Significance: Angiotensin Receptor Blockade Prevents the Developmental Programming of Cardiac Dysfunction

Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin–angiotensin system. Cardiac renin–angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin–angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague–Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3–P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-&bgr;/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin–angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions.Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin–angiotensin system. Cardiac renin–angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin–angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague–Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3–P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin–angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions. # Novelty and Significance {#article-title-40}