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. Author manuscript; available in PMC: 2009 Nov 25.
Published in final edited form as: Hypertension. 2008 May 12;52(1):44–50. doi: 10.1161/HYPERTENSIONAHA.107.092890

Developmental programming of hypertension: Insight from animal models of nutritional manipulation

Norma B Ojeda, Daniela Grigore, Barbara T Alexander
PMCID: PMC2782678  NIHMSID: NIHMS158776  PMID: 18474830

Abstract

Hypertension is a multi-factorial disorder thought to result from both genetic and environmental factors. Epidemiological studies suggest that cardiovascular diseases such as hypertension may be programmed in-utero. Experimental studies demonstrate that developmental programming occurs in response to a nutritional insult during fetal life and leads to slow fetal growth and permanent structural and pathophysiological changes that result in the development of hypertension and cardiovascular disease. A reduction in nephron number, hyperfiltration and increased susceptibility to renal injury, activation of the sympathetic and renin angiotensin systems, in addition to, increases in oxidative stress, are potential mediators of post-natal hypertension programmed in response to developmental insult. However, the quantitative importance and integration of these mechanistic pathways has not been clearly elucidated. Additionally, animal models of developmental programming exhibit sex differences with severity of the fetal insult critical to the phenotypic outcome. Recent studies suggest that sex hormones may play a critical role via modulation of the normal regulatory systems involved in the long-term control of arterial pressure. Investigation into sex differences in the developmental programming of hypertension may provide critical insight into the mechanisms linking sex hormones and factors important in blood pressure regulation. Understanding the complexity of the developmental programming of adult disease may lead to preventive measures and early detection of cardiovascular risk.

Keywords: intrauterine growth restriction, sex hormones, nephron number, angiotensin, renal nerves, oxidative stress

INTRODUCTION

Low birth weight (LBW), defined as a birth weight of 2.5 kg or less at term, is a major health issue within the United States today. The risk for LBW is greater within the black population than the white with a greater percentage of LBW occurring within the southern United States relative to other parts of the country 1. Babies born small for gestational age not only have a greater risk for survival at birth 2, 3, but based on numerous epidemiological studies, face long-term consequences such as increased risk for development of hypertension, cardiovascular disease, diabetes, and other health problems 4-6. Barker first proposed that an adverse environmental stimulus experienced during a critical period of fetal development leads to slow fetal growth and permanent structural and physiological changes in the fetus predisposing it to increased risk for development of hypertension and cardiovascular disease 7. Investigators utilizing animal models to induce an adverse fetal environment and mimic the human condition of slow fetal growth are providing convincing evidence to support the concept of developmental programming of adult disease 8-17. Although there is compelling epidemiological and experimental data which suggest that cardiovascular diseases such as hypertension may be programmed in utero, the underlying pathophysiological mechanisms remain unclear. Investigators utilize unique animal models of nutritional manipulation to induce slow fetal growth in order to examine the mechanisms linking birth weight and chronic adult disease such as hypertension. In this review we will discuss alterations in potential mechanistic pathways that evolve in response to fetal insult and lead to the developmental programming of hypertension highlighting insight provided by animal models of nutritional manipulation.

Animal models of nutritional manipulation during fetal life

Nutritional restriction is one of the most common experimental methods of fetal insult utilized for investigation into the mechanisms of programmed hypertension, and was one of the first to demonstrate that exposure to an adverse environment in utero leads to marked structural and physiological alterations 17. Importantly, this method of fetal insult was also one of the first to demonstrate that timing of the insult is critical to the programming response with a reduction in nephron number observed when the nutritional insult coincides with the nephrogenic period 8, 13, 18-21. Observations linking nutritional restriction during gestation with elevated blood pressure in offspring have been controversial 21-24. In the rat variations in dietary nutrient and protein balance are reported to contribute to differing blood pressure responses in offspring 22 with post-natal influences such as excessive weight gain exacerbating the effect 25. In humans, childhood growth is also a strong determinant of adult blood pressure demonstrating the importance of the post-natal environment on adult disease 26. In the sheep model of nutrient restriction birth weight rather than maternal diet may play a more critical role in the blood pressure response 23 with maternal body composition at the time of conception also critical to cardiovascular outcome 21. Animal models of reduced uteroplacental perfusion during late gestation also lead to an environment of undernutrition and hypertension in the intrauterine growth restricted (IUGR) offspring 10, 11. Contention exists in regards to the reproducibility of these models 27. However, consistent observations of IUGR are reported by numerous investigators 10-12, 28, 29; moreover, similar phenotypic outcomes such as a reduction in nephron number is observed in response to placental insufficiency, an observation that is not species specific 29-32. Overnutrition as a nutritional insult during fetal life also programs metabolic and cardiovascular dysfunction 33-35; implications critical due to the increased prevalence of obesity 36.

Importantly, these models of nutritional manipulation demonstrate characteristics reflective of the human condition of LBW including marked increases in blood pressure 10-15, 17, 19, 35, 37, 38 and reduced nephron number 13, 15, 18, 28, 29, 39. In humans, nephron number is directly correlated with birth weight and inversely correlated with blood pressure 40. Thus, models of nutritional insult, whether induced by direct manipulation of the gestational diet or through a reduction in uteroplacental perfusion, serve as relevant pathophysiological models for investigation into the mechanisms linking birth weight and blood pressure and will provide the basis for the discussion of potential mechanistic pathways presented in this review.

Mechanisms of developmental programming of hypertension

Hormones

Hormones are known to play a critical role in the proper development and growth of fetal tissues 41 and it is well documented that alterations in the intrauterine hormonal environment can lead to long-term effects on fetal outcome and cardiovascular health 42-46. In experimental studies, inappropriate exposure to testosterone during gestation results in IUGR44, impaired insulin sensitivity45, and cardiovascular dysfunction 46 demonstrating a critical role for sex hormones in the developmental programming of adult cardiovascular disease.

Models of developmental programming exhibit sex differences with severity of the fetal insult critical to the adult phenotypic outcome 18, 47. Whereas, severe protein restriction during gestation in the rat leads to hypertension and changes in renal structure in both male and female offspring15, 18, moderate protein restriction during gestation in the rat leads to marked increases in blood pressure and a reduction in nephron number in male, but not female offspring 15, 18, 47. Therefore, female offspring appear to be protected from an unfavorable phenotypic outcome in response to a moderate under-nutritional insult in utero. However, in models of programming induced by maternal diet-induced obesity, the prevalence for hypertension is greater 35 or present only 38 in female offspring indicating that sex differences in sensitivity to nutritional manipulation is insult specific. Sex differences in adult blood pressure are not observed in models of undernutrition programmed by placental insufficiency in the rat when assessed indirectly by tail cuff in conscious, restrained animals 11, 48. Conversely, sex differences in adult blood pressure are observed when measured directly by telemetry 49, 50; blood pressure after puberty is stabilized to normotensive levels in female IUGR, yet is further increased in male IUGR 49, 50. Castration abolishes hypertension in male IUGR 49; ovariectomy induces hypertension in female IUGR rats, an effect reverted by hormonal replacement therapy 50. Thus, sex differences in the blood pressure response to placental insufficiency in IUGR offspring indicate a potential role for sex hormones in mediating sex differences in the post-natal blood pressure response to fetal insult (Figure 1).

Figure 1.

Figure 1

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Potential mechanisms for the developmental programming of hypertension in response to nutritional manipulation during fetal development.

Sexual dimorphism is observed in human essential hypertension and in experimental models of hypertension 51-54 with a role for sex hormone involvement strongly indicated. Hypertension is less prevalent in pre-menopausal women as compared to age-matched men. However, after menopause the risk of hypertension increases with age 51, 52 suggesting that while the ovaries are functional women have a lower risk for hypertension and cardiovascular disease than men. Experimental studies suggest sex hormones play a mechanistic role in blood pressure control. Ovariectomy leads to hypertension in female rats normotensive to their male counterparts in some experimental models of hypertension 53, 54 suggesting an important role for estradiol in blood pressure regulation. Androgens exacerbate hypertension in the male spontaneously hypertensive rat (SHR)55; castration reduces blood pressure in male SHR 56 thus, indicating a role for androgens. Thus, sex hormones appear to contribute to sex differences in adult blood pressure regulation. Whether sex hormones are altered in LBW individuals is controversial 57-60. Moreover, few investigators have reported whether adult sex hormones are altered in response to fetal insult 61-66, nor have they examined the direct effect of sex hormones on post-natal hypertension in experimental models of developmental programming. Thus, the exact mechanism(s) by which sex hormones contribute to the developmental programming of blood pressure regulation has not been clearly elucidated, but may involve modulation of systems critical to the long term control of blood pressure regulation.

The renin angiotensin system

The renin angiotensin system (RAS) is a major regulator of blood pressure control and volume homeostasis 67. Numerous studies indicate that the RAS plays an important role in the etiology of hypertension programmed by in utero insult 15, 49, 50, 68-72 (Figure 1). A critical role for the central RAS is indicated in hypertension programmed in response to maternal undernutrition in the rat with marked increases in angiotensin type 1 receptor (AT1R) expression observed in areas of the brain critical to cardiovascular regulation 73 (Figure 2). In the kidneys temporal alterations in the RAS occur in response to fetal insult. A reduction in intrarenal renin and angiotensin II (ANG II) is observed at birth in response to maternal protein restriction in the rat 15 followed by post-natal up-regulation of the renal AT1R70, 72. In addition, inappropriate activation of the peripheral RAS, demonstrated by a marked increase in plasma renin activity (PRA), occurs after development of hypertension 68, 69. Importantly, hypertension is abolished by systemic blockade of the RAS 68, 69, 71 indicating that the RAS contributes to hypertension programmed in response to maternal nutrient restriction. In a model of undernutrition induced by placental insufficiency temporal alterations in the renal RAS are also observed with renal angiotensinogen and renin mRNA expression suppressed at birth, but markedly elevated in adulthood 74. Unlike models of maternal nutrient restriction, renal AT1R and ANG II expression as well as inappropriate activation of the peripheral RAS are not observed 49, 50, 74; yet, the importance of the RAS is indicated as hypertension is abolished by RAS blockade 49. Although the contribution of the RAS to the development of hypertension is not clearly defined, it may involve an increased responsiveness to ANG II. Androgens can augment renal vascular responses to ANG II 75. Elevated levels of testosterone are observed in male IUGR programmed in response to placental insufficiency49. Therefore, elevated levels of adult testosterone may be one mechanism by which sensitivity to ANG II is increased, and may also contribute to the enhanced intrarenal renin and angiotensinogen mRNA expression observed in adult male IUGR 76.

Figure 2.

Figure 2

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Potential renal mechanisms whereby developmental programming in response to in utero insult leads to development of hypertension.

Modulation of the RAS by estradiol may also contribute to sex differences in hypertension programmed by fetal insult. Estradiol is reported to downregulate tissue ACE 77 and AT1R mRNA expression 78 suggesting estradiol may reduce ANG II, a potent vasoconstrictor peptide critical for blood pressure regulation 67, 79. Estradiol may also alter the ACE2-dependent pathway 80, which generates ANG (1-7), a negative regulator of the vasoconstrictor effects of ANG II 79. Modulation of the RAS by estradiol may be one mechanism by which sex hormones play a protective role against an increase in blood pressure in adult female IUGR offspring in a model of undernutrition induced by placental insufficiency. Hypertension is induced by ovariectomy in female IUGR, but not female control offspring 50. ACE inhibition abolishes ovariectomy-induced hypertension 50 suggesting a critical role for the RAS. Normotensive adult female IUGR offspring exhibit a significant elevation in renal ACE2 mRNA expression that is decreased by ovariectomy with no effect observed in adult female control 50. Thus, loss of estradiol may decrease the vasodilator effect provided by the ACE2 pathway leading to an increase in blood pressure in adult female IUGR following ovariectomy. Therefore, permanent alterations in the RAS occur in response to fetal insult and contribute to the development of hypertension; modulation of the RAS by sex hormones is one mechanism that may contribute to sex differences in programmed hypertension (Figure 1).

The renal nerves

Many known regulatory mechanisms control sodium balance and alterations in sympathetic activity have sustained effects to reduce pressure natriuresis and result in long-term changes in arterial pressure 81, 82. However, whether sympathetic function contributes to hypertension in LBW individuals is controversial 83-86. Circulating levels of catecholamines, neurotransmitters which serve as an indirect marker of sympathetic nerve outflow, are increased in response to fetal undernutrition in models of developmental programming induced by both gestational protein restriction 87 and also placental insufficiency in the rat 88 and sheep 89. The importance of the renal nerves in the etiology of hypertension programmed by in utero insult was recently demonstrated whereby renal denervation normalized arterial pressure in adult male IUGR offspring in a model of placental insufficiency with no significant effect on blood pressure in adult control offspring 90. Therefore, these findings indicate the renal nerves play an important role in the etiology of hypertension programmed by fetal undernutrition induced by placental insufficiency (Figure 1). Increased sympathetic outflow including sustained increases in renal sympathetic nerve activity can also occur as a result of the actions of ANG II in regions of the brain critical for cardiovascular regulation 91. Thus, central activation of the RAS leading to an increase in RSNA may induce altered renal nerve development in IUGR offspring resulting in hypertension.

Oxidative stress

A decrease in bioavailability of antioxidants leading to an increase in oxidative stress is indicated to play an important role in essential and experimental hypertension 92, 93. Oxidative stress is increased in LBW children 94 suggesting that alterations in oxidant status may contribute to hypertension programmed in response to fetal insult. In experimental models of in utero exposure to undernutrition, hypertension is abolished by administration of the superoxide dismutase mimetic (SOD), tempol 95, or the lipid peroxidation inhibitor, lazaroid 96 implicating an important role for oxidative stress (Figure 1). ANG II stimulates oxidative stress through its AT1R 97. Thus, up-regulation of renal AT1R and inappropriate activation of the RAS may serve as a stimulus for increased oxidative stress in the developmental programming of hypertension.

Nephron number

A reduction in nephron number is a phenotypic outcome commonly observed in the fetal response to gestational insult in experimental models of undernutrition induced by maternal nutrient restriction 8, 14, 15, 20, 21, 98 and placental insufficiency 29-32. A reduction in nephron number leading to a reduction in renal excretory function is suggested to serve as a mechanism in the developmental programming of hypertension. Whether a reduced nephron complement could lead to hypertension was demonstrated in a study whereby removal of one kidney during the nephrogenic period in the rat led to adult hypertension 99. However, recent findings indicate that a reduction in nephron number is not always critical to the developmental programming of hypertension. A maternal diet rich in fat does not alter nephron number in offspring 100. Furthermore, an increase in glomerular volume is often observed in conjunction with reduced nephron number 18. Glomerular filtration rate (GFR) is not decreased in a rat models of maternal protein restriction 15 or placental insufficiency 10. Thus, compensatory hyperfiltration may occur in response to fewer nephrons at birth resulting in preservation of GFR 10, 15, 98 suggesting that factors other than a reduced nephron complement contribute to the etiology of hypertension programmed by in utero insult. Numerous factors including intrarenal sodium transport defects and/or abnormalities in the extrarenal control systems that regulate kidney function can mediate a reduction in renal sodium excretory function observed in hypertension 101. Thus, a sodium retaining defect not mediated by alterations in the filtered load of sodium may be the main contributor to a reduction in pressure natriuresis and hypertension programmed in response to adverse developmental influences (Figure 2). Whether a reduction in nephron number leading to a decrease in GFR contributes to hypertension programmed in response to fetal insult is unclear. Nevertheless, a reduction in nephron complement may diminish resistance to renal damage in adult life leading to an increased susceptibility to renal disease.

Susceptibility to renal disease

Progression of renal injury and disease is closely linked to hypertension. It is well established that the kidney exhibits increased vulnerability to fetal insult as evidenced by the association of reduced nephron number with IUGR in animal models of fetal nutrient manipulation 8, 14, 15, 20, 21, 29-32, 98 . However, recent studies indicate that susceptibility to renal disease is greater in LBW individuals 102, 103 with implications for a gender bias and a protective role for estradiol in women 104. Hypertension associated with an increase in urinary albuminuria 105, glomerulosclerosis, and histological determinants of renal damage 106, 107 is observed in offspring of nutrient restricted dams. Hypertension, proteinuria, and glomerulosclerosis are reduced by long-term post-natal Larginine supplementation; however, evidence of renal damage persists 106. Therefore, these studies indicate that increased susceptibility to renal damage is not just the result of hypertension, but may have an origin in fetal life. Furthermore, a reduction in nephron number at birth in conjunction with an increase in glomerular size and compensatory hyperfiltration may contribute to an increased susceptibility to renal injury, and enhance the later development of hypertension in LBW individuals (Figure 1).

Perspective

Insight provided by animal models of nutritional manipulation during fetal life suggests that slow fetal growth leads to alterations in the normal regulatory systems involved in the long-term control of blood pressure regulation. The pathogenesis of hypertension programmed by in utero insult is multifactorial and may involve intrinsic intrarenal defects or alterations in extrarenal regulatory systems critical to renal sodium excretory function. Moreover, a role for sex steroids is also demonstrated. Understanding the complexity of the fetal programming of adult disease may lead to preventive measures and early detection of cardiovascular risk in low birth weight individuals.

Acknowledgments

SOURCES OF FUNDING

Dr. Alexander is supported by NIH grants HL074927 and HL51971.

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