Pediatr Cardiol DOI 10.1007/s00246-015-1204-7

REVIEW ARTICLE

Programming of Essential Hypertension: What Pediatric Cardiologists Need to Know Joana Morgado1



Bruno Sanches2 • Rui Anjos3 • Constanc¸a Coelho4

Received: 6 March 2015 / Accepted: 14 May 2015 Ó Springer Science+Business Media New York 2015

Abstract Hypertension is recognized as one of the major contributing factors to cardiovascular disease, but its etiology remains incompletely understood. Known genetic and environmental influences can only explain a small part of the variability in cardiovascular disease risk. The missing heritability is currently one of the most important challenges in blood pressure and hypertension genetics. Recently, some promising approaches have emerged that move beyond the DNA sequence and focus on identification of blood pressure genes regulated by epigenetic mechanisms such as DNA methylation, histone modification and microRNAs. This review summarizes information on gene–environmental interactions that lead toward the developmental programming of hypertension with specific reference to epigenetics and provides pediatricians and pediatric cardiologists with a more complete understanding of its pathogenesis. Keywords Hypertension  Genes  Environment  Epigenetics

Introduction Globally, cardiovascular disease (CVD) accounts for approximately 17 million deaths a year, nearly one-third of the total number of deaths worldwide [15]. Of these 17 million, complications of hypertension account for 9.4 million [68]. Hypertension is responsible for at least 45 % of deaths due to heart disease and 51 % of deaths due to stroke. In 2008, approximately 40 % of adults aged 25 and above had been diagnosed with hypertension, and the number of people with the condition rose from 600 million in 1980 to one billion in 2008 [36]. According to the World Health Organization, if appropriate action is not taken, deaths due to cardiovascular disease are expected to rise further [1]. Hypertension has numerous causes, but its etiology remains elusive. Interactions of multiple genetic and environmental factors, as well as gene–gene interactions, modify various physiological systems responsible for blood pressure (BP) control [82]. Hypertension seems to develop as a consequence of errors in well-coordinated BP regulatory systems [56].

Aims & Joana Morgado [email protected] 1

Pediatrics Department, Hospital do Espı´rito Santo de E´vora, Largo Senhor da Pobreza, 7000-811 E´vora, Portugal

2

Pediatrics Department, Hospital Garcia de Orta, Almada, Portugal

3

Pediatric Cardiology Department, Hospital Santa Cruz, Lisbon, Portugal

4

Genetics Laboratory, Environmental Health Institute, Lisbon Medical School, Lisbon, Portugal

The aim of this review was to summarize what is currently known regarding gene–environmental interactions and epigenetics in the etiology of hypertension.

Methods An online search of papers published in English until April 30, 2014, was performed using the Medline online search with the following search criteria: ‘‘epigenetic AND

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hypertension.’’ A total of 270 papers were found. After reading all the abstracts, papers with inconclusive results, study design protocols and unrelated papers were discarded, resulting in 71 papers. Full reading of these 71 papers resulted in the selection of 48 extra papers. After full reading of all papers, the most relevant 100 papers were included in this review.

Essential Hypertension Is it Genetic? The genetic contribution to BP variation is estimated to range from 30 to 60 % [99, 106]. For complex diseases such as essential hypertension, positional cloning (i.e., fine mapping of linkage peaks often harboring a large number of genes) proved unsuccessful because the inheritance of these diseases does not follow a Mendelian pattern. The small contributions of individual genes and the heterogeneity of patients render genetic studies of essential hypertension difficult. However, and until now, several different genes have been found to play a role in hypertension in humans [24]—Table 1. Tomaszewski et al. used a custom-made gene-centric array with over 30,000 common and rare single nucleotide polymorphisms (SNPs) to genotype 2,020 European individuals from 520 nuclear families with 24-h ambulatory BP testing available. A total of 105 candidate genes for BP, with good genetic coverage of common variants, were present on the array. However, little evidence was

Table 1 Phenotype–gene relationships in essential hypertension [46]

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found for the involvement of the most frequently studied candidate genes for BP, such as those for the sympathetic nervous system and the renin–angiotensin system [107]. In two genome-wide association meta-analysis of multiple population cohorts [64, 77], six loci for systolic BP and 9 for diastolic BP were discovered, two of which overlapped, yielding 13 independent genome-wide significant signals. Only 2 of the 13 loci discovered could have been regarded as candidates for BP control, MTHFR and CYP17A1. However, without exception, the most significant SNPs representing these loci only explained a very small part of the total BP variance (B0.11 %). The first successful genome-wide association study (GWAS) for hypertension used a case– control design in a discovery sample of 1,621 hypertension cases and 1,699 controls, representing the top 2 % and bottom 20 % of the BP distribution in Sweden. Combined with follow-up validation analyses in 19,845 cases and 16,541 controls, a locus near the uromodulin (UMOD) gene was identified. UMOD is exclusively expressed in the kidney, suggesting that the discovered variant may have an effect on sodium homeostasis [82]. GWA studies have shown that the effects associated with individual common alleles are much smaller than expected (\1 %) [49], and the genetic architecture of common disease risk is not as simple as initially hypothesized [10]. Although there is no doubt that hypertension has a genetic component, the difficulty in identifying genes directly responsible for this disease strongly suggests the involvement of other factors, namely environmental and epigenetic.

Location

Phenotype

Gene/locus

1p36.12

{Hypertension, essential, susceptibility to}

ECE1

1q23.3

[Blood pressure regulation QTL]

RGS5

1q24.2

[Blood pressure regulation QTL]

ATP1B1

1q24.2

[Blood pressure regulation QTL]

SELE

1q42.2

{Hypertension, essential, susceptibility to}

AGT

2p25–p24

{Hypertension, essential, susceptibility to, 3}

HYT3

3q24

Hypertension, essential

AGTR1

4p16.3

{Hypertension, essential, salt-sensitive}

ADD1

5p13–q12

{Hypertension, essential, susceptibility to, 6}

HYT6

7q22.1

{Hypertension, salt-sensitive essential, susceptibility to}

CYP3A5

7q36.1

{Hypertension, susceptibility to}

NOS3

12p13.31 12p12.2–p12.1

{Hypertension, essential, susceptibility to} {Hypertension, essential, susceptibility to, 4}

GNB3 HYT4

15q

{Hypertension, essential, susceptibility to, 2}

HYT2

17q

{Hypertension, essential, susceptibility to, 1}

HYT1

17q11.2

{Hypertension, susceptibility to}

NOS2A

20q11–q13

{Hypertension, essential, susceptibility to, 5}

HYT5

20q13.13

Hypertension, essential

PTGIS

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The Developmental Origins of Health and Disease Hypothesis In 1989, David Barker et al. suggested that intrauterine environmental factors, mainly nutrition, could lead to permanent metabolic and structural changes in the fetus, influencing BP in adult life and increasing the risk of cardiovascular disease in adulthood. They retrospectively studied 10,636 men born in England and Wales between 1911 and 1930, with records of weight and length at birth and throughout the first year of life, as well as variables of mothers’ health and living conditions. The data generated clearly demonstrated an inverse relationship between birth weight and adult incidence of cardiovascular-related mortality and morbidities [3], suggesting that poor health and physique of mothers were important determinants of these risks. The main mechanistic hypothesis has long been that an impairment of intrauterine environment deprives the fetus from its optimal development leading to cardiovascular complications later in life [3]. When a fetus develops under suboptimal conditions, there is an adaptation to these conditions to guarantee immediate survival and to preserve vital functions at the expense of others, for example inducing peripheral insulin resistance to preserve glucose for vital organs while halting the development of others such as the kidneys or pancreas. Gluckman and Hanson have suggested that the changes induced may reflect an adaptive response of the fetus to environmental cues, acting through the process of developmental plasticity. This allows an organism to adjust its developmental program, resulting in long-term metabolic and physiologic changes in order to be better adapted to the future environment [37]. The resulting phenotype will not only depend on the type of insult, but also of its timing, as different organs present different critical windows of susceptibility to developmental modulation. One important feature of such adaptive changes during development is that different phenotypes can be generated from a single genome depending on the environment that the organism experiences [65].

Developmental Programming of Hypertension The early epidemiological data supporting the developmental origins of chronic non-communicable diseases focused on retrospective clinical studies that associated poor nutrition during development with a greater risk of adult cardiovascular disease, especially if the developmental and adult environments were dissimilar [4]. Despite large studies showing an inverse relationship between birth weight and adult BP [63, 101], others have failed to either show this relationship or show a relatively small impact in

terms of changes in mmHg/kg of birth weight [47]. The analysis of published findings clearly shows that there is a continuum of risk across the birth weight strata, with both extremes of birth weight associated with the highest risk of hypertension [78]. However, birth weight alone is an oversimplified marker of a ‘‘healthy’’ antenatal life [19], and individuals who are exposed to adverse in utero conditions do not have to manifest low birth weights to develop adult chronic medical conditions such as hypertension [38, 83]. Any individual newborn of lower weight at birth may have arrived at that particular weight via a number of routes [60]. Developmental changes arising before implantation are likely to affect many cell lineages, although adaptations later in gestation may compensate for the early changes and normalize birth weight [39]. It is now recognized that a low birth weight, used as a surrogate marker of poor nutrition in utero, is not essential for programming adult disease onset [75]. Maternal Nutrition The importance of maternal diet composition, as opposed to simple restriction, is supported by studies in populations from the UK, Jamaica and India, reporting increased BPs in children and adults born to mothers who had a lower proportion of caloric intake from animal protein during pregnancy [13], or who were iron-deficient during pregnancy, which reflects a poor nutritional status [29, 40, 101]. Godfrey et al. [40] have reported that the BPs of prepubescent Jamaican boys are inversely related to the triceps skinfold thickness and hemoglobin status of their mothers pre-pregnancy. The Dutch famine cohort shows that people who were small at birth have high BP later in life, and this BP was inversely associated with the protein/carbohydrate ratio of the average ration during the third trimester of pregnancy, whereas it was not associated with any absolute measure of intake during pregnancy [89, 90]. Children whose mothers consumed little protein in relation to carbohydrate during the third trimester of pregnancy had higher BPs in adulthood. This may imply that BP is more linked to variations in the balance of macronutrients in the maternal diet during gestation than to absolute amounts of nutrients and that programming might have occurred without significant modification of birth weight [78]. Animal studies in rats, mice and guinea-pigs consistently showed that fetal exposure to any form of undernutrition produces elevated BP [60], and similar observations in large animal species suggest that programming of cardiovascular function occurs in all mammals [41]. Administration of a low-protein (LP) diet to pregnant rats, either until term or weaning, has been seen to produce offspring of reduced birth weight with elevated systolic and

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diastolic BPs, as early as 4 weeks of age [59]—Fig. 1. Similarly, low-iron diets [32] or high-saturated fat diets [53] during rat pregnancy produce large effects on the BP of the offspring. When the diet is manipulated in such a way that the intakes of all nutrients are reduced in a balanced manner during pregnancy, the impact on BP of the subsequent offspring is still observed, but tends to be of a lower magnitude [54, 115]. It is currently known that the offspring of rats fed an LP diet will undergo a late-gestation retardation of growth, which affects particularly the development of lungs and kidneys [61]. In the postnatal period, these animals have an accelerated progression toward renal failure [79]. Increases in systolic BP were demonstrated following a period of protein restriction through either the period of oocyte maturation (-3.5 days until mating) or the preimplantation (0–3.5/4.5 days of gestation) period in both the mouse and rat [57, 111]. These outcomes are similar to those following an LP diet throughout pregnancy [116]. Preimplantation LP diet exposure also caused attenuated vascular responsiveness and changes in the renin–angiotensin system activity [112]. Using a maternal diet containing 70 % of the required energy from 6 weeks prior to mating until day 7 of pregnancy, late-gestation twin fetuses had increased BP [26]. It is clear that both human and animal studies support the importance of a balanced maternal diet in the health of the offspring and suggest that this diet should start before

Fig. 1 Possible effects of a maternal low-protein diet on the offspring

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the pregnancy. However, even in developed countries where women have ready access to contraceptives, it is estimated that 40–45 % of pregnancies are unplanned [76] and women may unknowingly expose their offspring to an adverse environment. While in utero nutrient restriction has been shown to promote hypertension, CVD, and chronic kidney disease in offspring, we are more commonly faced with maternal over-nutrition. In the last decade, fetal exposure to excess nutrients, often associated with maternal obesity and/or diabetes, has been identified as a risk factor for adult disease onset [72]. This has very important implications for the future health of Western nations, where the rates of obesity are increasing dramatically [55], and in developing societies, where populations are undergoing socioeconomic changes [11]. In industrialized societies, up to 25 % of mothers are obese, and in relatively recent studies, [40 % of women gained excessive weight during their pregnancies [74]. In a study by Filler et al. [28], high maternal prepregnancy body mass index and a high birth weight were the most powerful predictors of a higher BP in childhood. Early Postnatal Life Early postnatal life can also result in programming of adult-onset diseases through further modulation of the impact of an altered antenatal life environment, as discussed above, or in itself, through nutrition or prematurity. Postnatal nutritional programming is a concept proposed by Alan Lucas who showed a slight but significant increase in diastolic BP in 6- to 8-year-old children born at term but who were small for gestational age (SGA), with a birth weight \10th percentile [70]. These SGA children were randomly assigned to receive a nutrient enriched or a standard formula for the first 9 months of life, and results suggest that faster weight gain in infancy might have an adverse cardiovascular impact later in life [98]. Breastfeeding has been previously associated with lower adult BP in preterm neonates when compared with preterm formula [97]. The mechanisms underlying this observation are not fully understood, but it was suggested that it is related to a relatively slower growth observed in their cohort of breastfed infants. Simply changing maternal diet physiologically or pharmacologically does not necessarily result in hypertensive offspring. Critical windows in development that may determine later BP include embryogenesis and placentation, although the extent to which postnatal growth is subsequently altered is likely to be pivotal in determining long-term outcomes [105]. All these approaches have demonstrated that variation in the quality or quantity of nutrient provision in pregnancy and/or lactation has a major impact on tissue development and function and can

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promote both disease susceptibility and disease resistance. These effects are often independent of major changes in fetal growth [60].

that the plasticity of immature organisms contrasts with the ‘‘rigidity’’ of mature organisms [119]. Glucocorticoid Programming

The Kidney and Salt Sensitivity A number of animal and human studies have shown an important relationship between maternal malnutrition, low birth weight of infants and the development of kidney disease and hypertension in offspring [88]. The kidney is particularly affected by maternal under-nutrition. Growthrestricted infants exposed to an LP diet during pregnancy have smaller kidneys with fewer nephrons [73, 100] and prematurity also leads to reduced nephron number [102], which has been reported to be a predictor for the development of hypertension [30, 31, 71, 118]. The hypertension that develops in small birth weight individuals is often characterized by increased salt sensitivity [69], and females seem to be more susceptible than males. This sensitivity, in the model of protein restriction during pregnancy, has been associated by different groups with an increased expression of the Na?–K?–2Cl- symporter (NKCC2 or BSC1) in the ascending limb of the loop of Henle [113]. Up-regulation of this sodium transporter, leading to a higher amount of Na? reabsorbed and therefore hypertension, has also been described in glucocorticoid and placental dysfunction models of programming. Renal sympathetic nerves appear to play an important role in the pathogenesis of hypertension in this model, as denervation was able to abolish increased expression of Na? transporters and normalized BP [5, 20]. The Renin–Angiotensin System The renin–angiotensin system (RAS) has long been recognized as a primary regulator of arterial BP and is thought to play a pivotal role in the pathogenesis of human and experimental hypertension [48, 50]. ACE inhibitors or angiotensin type 1 (AT1) receptor antagonists as antihypertensive drugs used in a short-term treatment of young spontaneously hypertensive rats (SHR) fully prevented the development of hypertension later in life [45, 117]. Hypertension is also prevented by blockade of angiotensin II formation or administration of an AT1 receptor antagonist, from 2 to 4 weeks of age in LP-fed offspring [93, 94]. The effect of antihypertensive therapy with ACE inhibitors is age-dependent, insofar as in adult animals it only has transient effects. Treatment from the weaning period resulted in the prevention of hypertension development, and this antihypertensive effect was seen even 12 weeks after stopping the therapy. In adult animals, the effect on established hypertension was minimal, and there was no effect after treatment withdrawal. This supports the idea

One major hypothesis for early life physiological programming implicates fetal overexposure to stress hormones such as glucocorticoids [25]. Glucocorticoid receptors (GRs) are expressed in most fetal tissues from mid-gestation onwards [16] and in the placenta [103]. Fetal glucocorticoid levels are normally much lower than levels in the maternal circulation [12]. This is thought to be mediated by placental 11b-HSD2, a type 2 isoform of 11b-hydroxy-steroid dehydrogenase, which catalyzes the conversion of active glucocorticoids into their inactive metabolites [91]. The enzyme is not a complete barrier to maternal glucocorticoids, and studies in rats and humans indicate that the efficiency of placental 11b-HSD2 near term varies considerably. The lowest placental 11bHSD2 activity, and presumably the highest fetal exposure to maternal glucocorticoids, is seen in babies with the smallest birth weights [6]. Studies in rats have shown that exogenously administered corticosterone, resulting in circulating maternal corticosterone levels similar to those seen as a result of restraint stress, are associated with programming of hypertension in the absence of changes in birth weight, suggesting that levels of glucocorticoids associated with physiological stress may overcome the placental 11bHSD2 barrier, leading to effects on the developing fetus [25]. Even short-term prenatal exposure (2 days) to dexamethasone, which is not inactivated by 11b-HSD2 and crosses the placenta, or corticosterone, is associated with programmed effects on BP and renal development [81, 96], an observation paralleled in sheep [22]. Feeding a proteinrestricted diet to pregnant rats increased glucocorticoid receptor expression and reduced expression of 11b-HSD2 in the liver, lung, kidney and brain in the offspring [7]. Studies with the LP rat model show that down-regulation of 11b-HSD2 by under-nutrition may be the common pathway through which a broad range of nutritional insults produce a narrow and similar range of programmed responses. Maternal protein restriction in rodents reduces the activity of placental 11b-HSD2 [62], suggesting that this activity is influenced by maternal environmental factors and that other environmental insults, such as maternal malnutrition, may operate through glucocorticoids in exerting their programming effects [25]. Moreover, blockade of maternal glucocorticoid synthesis through pharmacological adrenalectomy prevents programming of hypertension in the offspring of LP-fed rats, demonstrating the glucocorticoid dependence of the nutritional effect [58]. This is supported by the observation that elevation of BP in the maternal protein restriction model is prevented by

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inhibition of maternal corticosterone synthesis during pregnancy [58]. It was shown in animal models that prenatal treatment with glucocorticoids may result in permanent decrease in nephron number [17, 85], altered RAS activity [44, 80], and increased expression of AT1 and AT2 receptors and angiotensin-converting enzyme [114, 120]. The human placenta produces corticotropin-releasing hormone (CRH), and increased CRH levels may contribute to intrauterine growth restriction and prematurity. Placental CRH secretion is stimulated by glucocorticoids. Thus, maternal stress is characterized by enhancement of both cortisol and CRH levels, which in turn may lead to fetal growth retardation [17]. Maternal stress, accompanied by elevated CRH and glucocorticoid concentrations, affects both the length of pregnancy and the hormonal environment of the developing fetus. Although most experimental and clinical studies support this fetal programming hypothesis in relation to adult hypertension, there is still controversy regarding the cause and mechanisms underlying this phenomenon. The basic molecular mechanism of how the environment can influence long-term gene regulation has only recently been addressed through epigenetic studies [43]. Epigenetics Epigenetics has been defined as the study of changes in gene expression that occur in the absence of a change in the DNA sequence itself [38] and include DNA methylation, histone modification and microRNAs. The epigenetic marks act alone or in combination with alter chromatin structure and function and ultimately promote or inhibit gene transcription. It is important to realize that the epigenetic variability of genetic information is part of the normal development and differentiation, and epigenetic processes are natural and essential for many physiological functions. Epigenetic modifications of gene expression play a key role in ensuring appropriate cellular differentiation, so that only the required genes are expressed in a given cell type. Epigenetics is also required for X-inactivation and for maintaining the allelespecific expression of imprinted genes [14, 86]. If they occur improperly, they can cause serious adverse health effects and hence the relevance of epigenetics in the study of human disease. Epigenetic changes constitute a mean by which interactions between genes and environment can occur, allowing cells to respond quickly to environmental changes, thus providing a clear link between genes and the environment. The main type of epigenetic modification is DNA methylation through methyl groups, an epigenetic factor found in some dietary sources. DNA methylation involves the addition of a methyl group to cytosines within CpG dinucleotides. CpG dinucleotides are often clustered within

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the promoter region of genes, but are also present in the genes and other gene-associated regions. In general, increased methylated CpG within the promoters is associated with transcriptional repression as it interferes with the binding of transcription factors, but it may also promote transcription when localized at gene exon sites [108]. Methylation can be transient and can change rapidly during the lifespan of a cell or an organism, but it can be completely permanent if it is set early in the development of the embryo. Another largely permanent chemical modification is histone acetylation occurring when the binding of epigenetic factors to histone ‘‘tails’’ alters the extent to which DNA is wrapped around histones and the availability of genes in the DNA to be activated. Reversible changes in chromatin organization influence gene expression: genes are actively transcribed when the chromatin is open, but silent when it is condensed [92]. These factors and processes can have effects on human health, possibly resulting in cancer, autoimmune diseases, mental disorders, cardiovascular diseases or other illnesses. In addition to chromatin remodeling, regulatory non-coding RNAs such as microRNAs play a crucial role in the regulation of gene expression [2]. MicroRNAs are small RNAs, approximately 22 nucleotides in length, that repress the expression of mRNAs with which they are entirely or partially complementary [34], and are involved in processes such as cellular proliferation, apoptosis, differentiation and other important processes through degradation or translational inhibition of their target mRNAs. MicroRNAs may directly regulate up to a third of the genes in the human genome. Nuclear transcription of microRNA genes leads to generation of double-stranded RNAs, which are important for generation of the tightly packed, transcriptionally inactive heterochromatin and gene silencing [42]. Epigenetic mechanisms are affected by several factors and processes including in utero and childhood development, environmental chemicals, drugs and pharmaceuticals, aging and diet [56], and some epigenetic modifications, in particular DNA methylation, can be stably propagated through numerous cell divisions [11]. Extensive epigenetic reprogramming takes place during gametogenesis, but some epigenetic signatures can escape this process and are transmitted across generations. Differential timing of remethylation during gametogenesis may have implications for the relative paternal versus maternal epigenetic effect on the phenotype of the offspring. The early post-conceptional period is also a crucial time for establishment of DNA methylation patterns. After fertilization, rapid demethylation changes in the paternal genome take place, except in paternally imprinted genes, heterochromatin around some centromeres and some repetitive elements. Some forms of epigenetic modification are transmitted, but others may be ‘‘erased’’ or ‘‘reset’’, depending on a variety of factors [87, 104].

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Fig. 2 Schematic representation of a pathway through which adverse maternal environment may result in adult disease

Epigenetic profiles are, to a certain extent, affected by genetic variants. DNA sequence variations may render certain loci more or less prone to methylation, and a recent study showed that 0.16 % of SNPs in the human genome are associated with allele-specific methylation changes [52]. Nutritional and other environmental challenges may affect epigenetic marks in a variety of ways. They may change the availability of the common methyl donor, Sadenosylmethionine, or alter the expression or activity of epigenetic modifiers [2]. DNA methylation patterns have been reported to be sensitive to methyl -diets [35, 84] or to variations in other components of one-carbon metabolism, such as folic acid [18]. It has been shown that a maternal LP diet is associated with reduced global methylation, and it may be that aminoacid deficiency, such as the glycine required to generate methyl donors, underlies such changes [51]. A consistent LP diet supplemented with folic acid, glycine or urea inhibited the detrimental effects of this diet [51, 66]. Folic acid plays a crucial role in cell proliferation and mitosis, including the production of red blood cells, and is crucially required in pregnancy. In the fetus, folic acid helps the formation of the neural tube and confers protection against various birth defects. Besides folic acid, several dietary nitrogen supplements (e.g., glycine and urea) might also play a protective role in normal cardiovascular development and the maintenance of normal BP [51]. The Missing BP Heritability Several epidemiological and clinical peculiarities of essential hypertension, such as the incomplete concordance between monozygotic twins and its late onset and

progressive nature, are difficult to fully explain with traditional DNA sequence-based approaches. These observations may point to the involvement of epigenetic factors in hypertension development [109]. Finding suitable answers to the missing heritability enigma is currently the most important challenge in BP and hypertension genetics [110]. Animal models representing epigenetic origins of chronic metabolic disease have generally employed maternal alterations in nutrition during the pre- and postconceptional period. Studies in sheep show that clinically relevant reductions in folic acid and methionine around the time of conception lead to widespread changes in methylation (mostly hypomethylation) which in turn leads to increased adiposity, insulin resistance, reduced immune function and high BP [95]. Ding et al. [21] studied the influence of a high-salt diet during pregnancy on the development of the heart, and DNA methylation in the fetal heart tissue related to the subtype of angiotensin receptors. Following exposure to high salt, average methylation was lowered and the five affected CpG sites were linked to the AT1b promoter in the fetal heart. In comparison, in the control group, the same five CpG sites showed normal levels of methylation. The epigenetic change at the CpG sites may contribute to the alteration of the angiotensin II receptors in the fetal heart. The results suggest a relationship between high-salt diet in pregnancy and developmental changes of the cardiac cells and the renin– angiotensin system [21]. Feeding an LP diet or creating utero-placental insufficiency in pregnant rats causes DNA methylation responses, which manifest as endothelial dysfunction, increased angiotensin II type 1 receptor expression in the kidney and adrenal gland, hypertension, and reduced number of renal glomeruli in the progeny [8, 38]. Bogdarina et al. have

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demonstrated that maternal LP diet in pregnancy leading to the development of hypertension in the offspring was associated with reduced methylation and increased expression of the AT1b receptor gene (AGTR1b) in the rat adrenal gland. These findings suggest a link between fetal insults to epigenetic modification of genes and the resultant alteration of gene expression in adult life, ultimately leading to the development of hypertension [8]. In 2010, Bogdarina et al. reported that when the mothers receive metyrapone, an 11 beta-hydroxylase inhibitor, during the first 2 weeks of pregnancy, the hypertension, the increased AGTR1b expression and the reduced DNA methylation were all normalized. The findings of this study are, therefore, highly suggestive of the maternal pituitary–adrenal axis playing a central role in mediating the adverse effects of the LP diet [9]. In pregnant rats, protein restriction during gestation reduces methylation of the promoter region of the gene that codes for the glucocorticoid receptor in offspring liver cells [27, 67]. This leads to the amplification of the liver’s metabolite response to stress hormones. Indeed, one of the most plausible explanations for a resetting of cardiovascular control after exposure to nutrient restriction in utero resides within centrally, rather than peripherally, mediated adaptations [33]. Thus, an increased expression of the angiotensin I receptor within the brain stem may act to reset cardiovascular responsiveness [23]. Given all the above, there is no doubt that essential hypertension remains a challenge, with most of the heritability still missing—Fig. 2.

Conclusion The discovery of epigenetic mechanisms was a paradigm shifting event, in that it was realized that DNA sequence is not the sole determinant of phenotype. There is now evidence that epigenetic mechanisms allow the developing fetus to adapt to cues from the mother and adjust its developmental trajectory to produce a phenotype matched to the predicted postnatal environment. Environmental changes in the intrauterine period or shortly after birth may lead to altered gene expression via epigenetic mechanisms, resulting in an increased susceptibility to chronic disease in adulthood, namely hypertension. Despite the different initial insults, the final consequences for the offspring in adulthood are similar. It is evident from a body of experimental data that the restriction of major environmental risk factors could be effective in the prevention of hypertension mainly if applied in the precise critical periods. Proper monitoring of nutrition and health, during the periconceptional, prenatal and postnatal periods is of the utmost importance. Pregnancy should be well planned as the period around the time

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of conception and early embryonic development represents a time when a woman may unknowingly expose her offspring to an adverse environment. Women should be advised to control their diet and lifestyle and to avoid stress before and during pregnancy. Women should be encouraged to breastfeed, given this might contribute to the reduction of cardiovascular morbidity among susceptible individuals. The genetic architecture of BP regulation and essential hypertension has proved even more challenging than other complex traits and diseases, with most of the heritability still missing. The epigenetic mechanisms underlying fetal programming are only beginning to be unraveled. Future studies will define the molecular pathways leading to this phenomenon. Conflict of interest of interest.

The authors declare that they have no conflict

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Programming of Essential Hypertension: What Pediatric Cardiologists Need to Know.

Hypertension is recognized as one of the major contributing factors to cardiovascular disease, but its etiology remains incompletely understood. Known...
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