Sex differences in the fetal programming of hypertension

Background: Numerous clinical and experimental studies support the hypothesis that the intrauterine environment is an important determinant of cardiovascular disease and hypertension.Objective: This review examined the mechanisms linking an adverse fetal environment and increased risk for chronic disease in adulthood with an emphasis on gender differences and the role of sex hormones in mediating sexual dimorphism in response to a suboptimal fetal environment.Methods: This review focuses on current findings from the PubMed database regarding animal models of fetal programming of hypertension, sex differences in phenotypic outcomes, and potential mechanisms in offspring of mothers exposed to an adverse insult during gestation. For the years 1988 to 2007, the database was searched using the following terms: fetal programming, intrauterine growth restriction, low birth weight, sex differences, estradiol, testosterone, high blood pressure, and hypertension.Results: The mechanisms involved in the fetal programming of adult disease are multifactorial and include alterations in the regulatory systems affecting the long-tterm control of arterial pressure. Sex differences have been observed in animal models of fetal programming, and recent studies suggest that sex hormones may modulate activity of regulatory systems, leading to a lower incidence of hypertension and vascular dysfunction in females compared with males.Conclusions: Animal models of fetal programming provide critical support for the inverse relationship between birth weight and blood pressure. Experimental models demonstrate that sex differences are observed in the pathophysiologic response to an adverse fetal environment. A role for sex hormone involvement is strongly suggested,with modulation of the renin-angiotensin system as a possible mechanism.     

Kidney development and the fetal programming of adult disease

Recent evidence, from both epidemiological and animal experimental studies, suggest that the very first environment, the intrauterine, is extremely important in determining the future health of the individual. Genetic and 'lifestyle' factors impinge on, and can exacerbate, a 'programming' effect of an adverse fetal environment. In this review, we present compelling evidence to suggest that one of the major organs affected by an unfavourable prenatal environment is the kidney. Many of the factors that can affect fetal renal development (i.e. exposure to excess glucocorticoids, insufficient vitamin A, protein/calorie malnutrition (in rats) and alterations in the intrarenal renin angiotensinogen system), also produce hypertension in the adult animal. When nephron number is compromised during kidney development, maladaptive functional changes occur and can lead, eventually, to hypertension and/or renal disease. Surprisingly, it is during the very earliest stages of kidney development that the vulnerability to these effects occurs.     

Embryonic programming of heart disease in response to obesity during pregnancy

Obesity during pregnancy programs adult-onset heart disease in the offspring. Clinical studies indicate that exposure to an adverse environment in utero during early, as compared to late, gestation leads to a higher prevalence of adult-onset heart disease. This suggests that the early developing heart is particularly sensitive to an adverse environment. Accordingly, growing evidence from clinical studies and animal models demonstrates that obesity during pregnancy alters the function of the fetal heart, programming a higher risk of cardiovascular disease later in life. Moreover, gene expression patterns and signaling pathways that promote initiation and progression of cardiovascular disease are altered in the hearts in offspring born to obese mothers. However, the mechanisms mediating the long-term effects of an adverse environment in utero on the developing heart leading to adult-onset disease are not clear. Here, we review clinical and experimental evidence documenting the effects of maternal obesity during pregnancy on the fetal and post-natal heart and emphasize on the potential mechanisms of disease programming.     

Blood pressure follows the kidney

Epidemiological and experimental data strongly suggest that cardiovascular diseases can originate from an aberrant environment during fetal development, a phenomenon referred to as perinatal programming. This review will focus on the role of the kidneys in determining blood pressure, and how (re)programming the renal development can persistently ameliorate hereditary hypertension. By combining physiologic and genomic studies we have discovered some candidate pathways suited for (re)programming the development of hypertension. This sets the stage for mechanistic analysis in future studies.     

Animal models that elucidate basic principles of the developmental origins of adult diseases

Human epidemiological and animal laboratory studies show that suboptimal environments in the womb and during early neonatal life alter development and predispose the individual to lifelong health problems. The concept of the developmental origins of adult diseases has become well accepted because of the compelling animal studies that have precisely defined the outcomes of specific exposures such as nutrient restriction, overfeeding during pregnancy, maternal stress, and exogenously administered glucocorticoids. This review focuses on the use of animal models to evaluate exposures, mechanisms, and outcomes involved in developmental programming of hypertension, diabetes, obesity, and altered pituitary-adrenal function in offspring in later life. Ten principles of developmental programming are described as fundamental, regardless of the exposure during development and the physiological system involved in the altered outcome. The 10 principles are discussed in the context of the physiological systems involved and the animal model studies that have been conducted to evaluate exposures, mechanisms, and outcomes. For example, the fetus responds to challenges such as hypoxia and nutrient restriction in ways that help to ensure its survival, but this "developmental plasticity" may have long-term consequences that may not be beneficial in adult life. To understand developmental programming, which represents the interaction of nature and nurture, it is necessary to integrate whole animal systems physiology, in vitro cellular biology, and genomic and proteomic approaches, and to use animal models that are carefully characterized and appropriate for the questions under study. Animal models play an important role in this evaluation because they permit combined in vivo and in vitro study at different critical time windows during the exposure and the ensuing developmental responses.     

Embryonic and fetal programming of physiological disorders in adulthood

In the past decade, data from numerous epidemiological studies have indicated strong inverse associations between birth weight and risk of coronary heart disease, hypertension, type 2-diabetes, and other diseases in adulthood. The "Barker hypothesis" thus postulates that a number of organ structures and functions undergo programming during embryonic and fetal life. This developmental programming determines the set points of physiological and metabolic responses in adult life. Alterations of nutrient availability during gestation may lead to developmental adaptations, via hormonal maneuvers by the embryo and fetus that readjust these set points. These adaptive measures have short-term benefits to the embryo and fetus, so that the newborn will be better prepared for the adverse environment (e.g., undernutrition). However, adequate nutritional support during postnatal life that enables catch-up growth may create metabolic conflicts that predispose the adult to aberrant physiological functions and, ultimately, increased risk of disease. It is plausible that other adverse in utero conditions, including exposure to developmental toxicants, may similarly alter adult disease susceptibility. This article provides an overview of the Barker hypothesis, its supporting evidence, the current advances in understanding the biological mechanisms underlying this phenomenon, and its implications for developmental toxicology.     

Blood pressure follows the kidney: Perinatal influences on hereditary hypertension

Epidemiological and experimental data strongly suggest that cardiovascular diseases can originate from an aberrant environment during fetal development, a phenomenon referred to as perinatal programming. This review will focus on the role of the kidneys in determining blood pressure, and how (re)programming the renal development can persistently ameliorate hereditary hypertension. By combining physiologic and genomic studies we have discovered some candidate pathways suited for (re)programming the development of hypertension. This sets the stage for mechanistic analysis in future studies.Key words: perinatal development, spontaneously hypertensive rat, citrulline, nitric oxide, hypertension     

Maternal inflammation, growth retardation, and preterm birth: insights into adult cardiovascular disease

The "fetal origin of adult disease Hypothesis" originally described by Barker et al. identified the relationship between impaired in utero growth and adult cardiovascular disease risk and death. Since then, numerous clinical and experimental studies have confirmed that early developmental influences can lead to cardiovascular, pulmonary, metabolic, and psychological diseases during adulthood with and without alterations in birth weight. This so called "fetal programming" includes developmental disruption, immediate adaptation, or predictive adaptation and can lead to epigenetic changes affecting a specific organ or overall health. The intrauterine environment is dramatically impacted by the overall maternal health. Both premature birth or low birth weight can result from a variety of maternal conditions including undernutrition or dysnutrition, metabolic diseases, chronic maternal stresses induced by infections and inflammation, as well as hypercholesterolemia and smoking. Numerous animal studies have supported the importance of both maternal health and maternal environment on the long term outcomes of the offspring. With increasing rates of obesity and diabetes and survival of preterm infants born at early gestational ages, the need to elucidate mechanisms responsible for programming of adult cardiovascular disease is essential for the treatment of upcoming generations.     

Maternal environment and the reproductive function of the offspring

Fetal programming of metabolic diseases is now a well established concept. The scope of the Developmental Origins of Health and Disease has, however, widened and led to the identification of new targets of fetal programming, notably effects on reproductive function. Epidemiologic studies about maternal nutrition and effects on offspring's fertility are rare, but a link between impaired fetal growth, possibly caused by maternal malnutrition, and reproductive function, has been established. The methodologic limitations inherent to human epidemiologic studies can be complemented through the use of animal models, which enable experimental studies on maternal environment and its effect on reproductive functions of the offspring. Altogether, an interaction between inappropriate maternal nutrition (excess or reduced nutritional intake, micronutrient unbalance, or alcohol intake) and reproductive maturation of the offspring has been shown in a majority of experiments as summarized in this review. The exact processes through which maternal nutrition or maternal environment affect reproductive function in the offspring remain unclear but epigenetic modifications are a clear link. Further studies are needed to better understand the mechanisms involved, identify the crucial critical periods, and prevent or treat the adverse effects.     

Low birth weight increases susceptibility to renal injury in a rat model of mild ischemia-reperfusion

Renal injury due to ischemia-reperfusion (I/R) is the major cause of acute kidney injury. Whether enhanced susceptibility to renal injury due to I/R can be programmed during fetal life is unknown. Epidemiological studies indicate that low birth weight (LBW) individuals are more susceptible to renal injury than normal birth weight (NBW) individuals. Thus, the aim of this study was to test the hypothesis that LBW is associated with an increased susceptibility to renal injury induced by mild renal I/R (15-min ischemia). Systemic and renal hemodynamic parameters were determined in NBW and LBW adult male rats after mild renal I/R; renal superoxide production and tubular injury were also assessed. A subgroup was pretreated with tempol, a superoxide dismutase mimetic, initiated 15 min before ischemia. Mild renal I/R did not alter renal hemodynamic parameters, induce tubular injury, or induce superoxide production in NBW rats. However, renal hemodynamic parameters declined, superoxide production increased, and histological indicators of tubular injury were present following mild renal I/R in LBW rats. Acute treatment with tempol prevented these alterations in LBW rats subjected to mild renal I/R. Thus, these findings suggest that adverse conditions during fetal life can compromise the renal response to subtle insults leading to an increased susceptibility to renal injury, suggesting that LBW individuals may be an "at risk" population for renal disease. Additionally, the outcome of tempol treatment proposes a possible mechanistic pathway involved in mediating enhanced susceptibility to renal injury programmed during fetal life.     

Influence of fetal environment on kidney development.

Several lines of evidence, mostly derived from animal studies, indicate that changes in fetal environment may affect renal development. Besides maternal hyperglycemia or drug exposure, that were recently found to alter nephrogenesis, changes in vitamin A supply to the fetus may prove to be responsible for most of the variations in nephron number found in the population. A low vitamin A status in the fetus may be a major cause of inborn nephron deficit, either as a feature of intrauterine growth retardation or independently of growth retardation. The possibility that vitamin A status may also influence renal vascular development is raised. We suggest that low vitamin A supply to the fetus plays a role in the intrauterine programming of chronic renal disease and hypertension.     

Prenatal exposure to glucocorticoids and adult disease

There is evidence to suggest that an individual's susceptibility to cardiovascular disease cannot be entirely explained by differences in life style factors (i.e., low physical activity, high fat/salt diet), or genetic causes, but may also be influenced by factors encountered during intrauterine life. Epidemiological studies found the link between low birth weight for gestational age (a broad index of sub-optimal intrauterine environment) and increased incidence of cardiovascular and metabolic diseases in adulthood. Many animal models in which the intrauterine environment was altered during early/late or throughout gestation demonstrated long-term effects on adult health. In general stress in early gestation is more likely to be associated with adult cardiovascular disease including hypertension, whereas late gestation stress may also be associated with adult hypotension in addition to metabolic/endocrine abnormalities. Two systems have been widely hypothesised to serve as mechanisms via which adverse prenatal influences impinge on adult cardiovascular and metabolic disease; hippocampal-hypothalamo-pituitary-adrenal axis (HHPA) and renin-angiotensin system (RAS). Interestingly, at least in our animal model of adult hypertension after brief/early prenatal glucocorticoid exposure, HHPA axis is not altered when studied either in late gestation or at several stages during adulthood. However, our more recent results, using the same animal model, suggest a major role for the central and renal RAS. This review will mainly focus on animal models and potential mechanisms via which a perturbed intrauterine environment (undernutrition or steroid exposure) lead to adult cardiovascular and/or metabolic disease.     

The early life environment and the epigenome

Several lines of evidence point to the early origin of adult onset disease. A key question is: what are the mechanisms that mediate the effects of the early environment on our health? Another important question is: what is the impact of the environment during adulthood and how reversible are the effects of early life later in life? The genome is programmed by the epigenome, which is comprised of chromatin, a covalent modification of DNA by methylation and noncoding RNAs. The epigenome is sculpted during gestation, resulting in the diversity of gene expression programs in the distinct cell types of the organism. Recent data suggest that epigenetic programming of gene expression profiles is sensitive to the early-life environment and that both the chemical and social environment early in life could affect the manner by which the genome is programmed by the epigenome. We propose that epigenetic alterations early in life can have a life-long lasting impact on gene expression and thus on the phenotype, including susceptibility to disease. We will discuss data from animal models as well as recent data from human studies supporting the hypothesis that early life social-adversity leaves its marks on our epigenome and affects stress responsivity, health, and mental health later in life.     

Transgenerational effects of maternal diet on metabolic and reproductive ageing

The early-life environment, in particular maternal diet during pregnancy, influences a wide range of organs and systems in adult offspring. Mounting evidence suggests that developmental programming can also influence health and disease in grand-offspring. Transgenerational effects can be defined as those persisting into an F2 generation, where the F0 mother experiences suboptimal diet during her pregnancy. In this review, we critically examine evidence for transgenerational developmental programming effects in human populations, focusing on metabolic and reproductive outcomes. We discuss evidence from historical cohorts suggesting that grandchildren of women exposed to famine and other dietary alterations during pregnancy may experience increased rates of later health complications than their control counterparts. The methodological difficulties with transgenerational studies in human cohorts are explored. In particular, the problems with assessing reproductive outcomes in human populations are discussed. In light of the relative paucity of evidence available from human cohorts, we consider key insights from transgenerational experimental animal models of developmental programming by maternal diet; data are drawn from a range of rodent models, as well as the guinea-pig and the sheep. The evidence for different potential mechanisms of transgenerational inheritance or re-propagation of developmental programming effects is evaluated. Transgenerational effects could be transmitted through methylation of the gametes via the paternal and maternal lineage, as well as other possible mechanisms via the maternal lineage. Finally, future directions for exploring these underlying mechanisms further are proposed, including utilizing large, well-characterized, prospective pregnancy cohorts that include biobanks, which have been established in various populations during the last few decades.     

Maternal low-protein diet in rat pregnancy programs blood pressure through sex-specific mechanisms

Animal models support human epidemiological studies in demonstrating a relationship between impaired fetal growth and risk of adult hypertension. Undernutrition during pregnancy exerts programming effects on the developing kidney, and modulation of angiotensin receptor (ATR) expression has been observed persisting into adult life. Fetal overexposure to glucocorticoids is thought to be central to the nutritional programming of blood pressure and may act through an interaction with ATR expression. Pregnant female Wistar rats were fed a control (n = 6) or a maternal low-protein diet (MLP; n = 17) throughout pregnancy. The glucocorticoid dependency of MLP effects was tested using metyrapone, an inhibitor of corticosterone synthesis. MLP-fed rats were injected twice daily with metyrapone, metyrapone plus corticosterone, or vehicle over days 1-14 of pregnancy. At delivery, all animals were fed standard laboratory chow. MLP-exposed offspring 4 wk of age exhibited increased systolic blood pressure compared with controls (P < 0.05), which proved to be glucocorticoid dependent in males only. AT(1)R mRNA expression was independent of in utero dietary treatment. AT(2)R mRNA expression was downregulated in MLP-exposed females only (P < 0.05) and in a glucocorticoid-independent manner. Male offspring exhibited glucocorticoid-dependent hypertension with no modulation of renal ATR mRNA expression. In contrast, female offspring exhibited glucocorticoid-independent hypertension associated with reduced expression of renal AT(2)R mRNA. These data do not support the hypothesis that an interaction between glucocorticoid and ATR mRNA expression underlies the nutritional programming of blood pressure but instead suggest two independent mechanisms acting in a sex-specific manner.     

Nutritional programming of blood pressure and renal morphology

A range of epidemiological evidence from several diverse populations, supports the hypothesis that risk of essential hypertension, coronary heart disease and non-insulin dependent diabetes is, in part, programmed by intrauterine nutritional status. Animal models developed to investigate the mechanisms that are responsible for such programming are becoming more important as challenges to the epidemiological data become more robust. With strong evidence from animal studies it is now widely accepted that maternal nutritional status in pregnancy is a major programming influence upon the fetus. This paper considers the hypothesis that renal structure and function are determined by prenatal nutrition and that this is a key mechanism in the programming of hypertension. The feeding of low protein diets or other insults in pregnancy that have an impact upon the development of cardiovascular functions, also appears to impact upon nephron number. In the sheep nephron number is related to weight at birth following nutrient restriction, and in the rat low protein diets reduce nephron number by approximately 30%. However, it is possible that hypertension and reduced renal reserve merely coincide and are not causally associated. A study of rats fed low protein diets supplemented with additional nitrogen sources found that whilst only glycine could reverse the hypertensive effects of low protein diets, all supplements could normalise nephron number. The evidence thus suggests that prenatal undernutrition may programme renal structure in later life, but that renal programming is not one of the primary mechanisms leading to hypertension.     

Substrate-energy metabolism and metabolic risk factors for cardiovascular disease in relation to fetal growth and adult body composition

The effect of fetal programming on intermediary metabolism is uncertain. Therefore, we examined whether fetal programming affects oxidative and nonoxidative macronutrient metabolism and the prevalence of the metabolic syndrome in adult life. Healthy older men, aged 64-72 years, with either a lower birth weight (LBW, or=75th %ile; n = 13) had measurements of 1) net oxidative metabolism using indirect calorimetry before and for 6 h after a mixed meal (3,720 kJ) and 2) postprandial oxidation of exogenous [13C]palmitic acid. Body composition was measured using dual-energy X-ray absorptiometry. After adjustment for current weight and height, the LBW group had a lower resting energy expenditure (REE) in the preprandial (4.01 vs. 4.54 kJ/min, P = 0.015) and postprandial state (4.60 vs. 5.20 kJ/min, P = 0.004), and less fat-free mass than the HBW group. The BW category was a significant, independent, and better predictor of REE than weight plus height. There were no significant differences between groups in net oxidative and nonoxidative macronutrient (protein, fat, carbohydrate) metabolism (or of exogenous [13C]palmitate) or in the prevalence of the metabolic syndrome, which was present almost twice as commonly in the LBW than in the HBW group. The study suggests that fetal programming affects both pre- and postprandial EE in older life by mechanisms that are at least partly related to the mass of the fat-free body. BW was found to be a significant predictor of REE that was independent of adult weight plus height.     

Intra-uterine origins of type 2 diabetes

Epidemiological studies have linked low birth weight with an increased risk of type 2 diabetes in later life. This finding has been observed in many populations worldwide, in many different ethnic and socio-economic groups. These studies led to the proposal of the 'thrifty phenotype hypothesis' that suggests that the foetal environment plays a major role in mediating this relationship. Here we review the human studies and those in animal models which support the 'thrifty phenotype hypothesis'. Molecular pathways underlying the mechanisms by which a suboptimal foetal environment leads to increased risk of type 2 diabetes are discussed, along with future directions outlining how these pathways and programming events can be further dissected to discover plausible intervention strategies to reduce type 2 diabetes.