An adverse environment during intrauterine has an important effect on the later risk of cardiovascular disease and more specifically epidemiological studies have strongly suggested that an adverse intrauterine environment may lead to adult hypertension (Role of fetal programming in the development of hypertension, 2008). Hypertension is a major risk factor for cardiovascular diseases such as heart attack, congestive heart failure, stroke and peripheral vascular disease.
Several experimental studies have shown a significant inverse relation between birth weight and subsequent levels of blood pressure (Association between birth weight and adult blood pressure in twins: historical cohort study, 1999). Compared with higher birth weight babies, low birth weight babies have been shown to have higher levels of blood pressure as children, adolescents, and adults, but the association being more pronounced with age. It is hypothesized that some adverse aspect or aspects of intrauterine life, such as nutritional deficiencies at critical periods of fetal growth, programme the fetus to have higher levels of blood pressure after birth. Because these associations are independent of adult lifestyle or size, it has been postulated that a reduced intrauterine nutrient supply perturbs fetal growth and, concomitantly, alters or programmes the structure and function of developing systems. According to this hypothesis, an impairment of intrauterine environment deprives the fetus form its optimal development leading to the cardiovascular complication in later life.
A reduced fetal nutrient supply may be a consequence of:
1. maternal nutritional deficiencies; these can be caused by either restriction of total food intake (global food restriction) during all or part of pregnancy or restriction of a particular nutrient, usually protein, throughout or during a specific time window of pregnancy. Global food restriction for all or part of gestation can lead to increased blood pressure in the offspring, but it is not clear whether the important factor in these diets is the overall reduction in calories or the reduction in a specific nutrient. Speaking of proteins, mild or modest or severe restriction of this nutrient during pregnancy has been reported to increase offspring arterial pressure in adulthood.
2. interference with placental function or poor placental function.
Glucocorticoids
One outcome of either a suboptimal placental or maternal nutrient supply is exposure of the fetus to excess glucocorticoids, which act to restrict fetal growth and to programme permanent changes in the cardiovascular, endocrine and metabolic systems. Some researchers have proposed that the key is exactly this increased fetal exposure to glucocorticoids, caused by elevated maternal glucocorticoid levels, by increased passage of glucocorticoids to the fetus, or by activation of the fetal hypothalamic-pituitary-adrenal axis (HPA) (Glucocorticoid exposure in utero: A new model for adult hypertension, 1993). Fetal corticosterone levels have been reported to be increased, in several studies, by maternal food restriction but not by maternal protein restriction (The maternal endocrine environment in the low-protein model of intra-uterine growth restriction, 2003).
Separation of the fetal circulation from glucocorticoids of maternal origin is crucial to the normal development of the fetal hypothalamic–pituitary–adrenal axis, and also ensures that the correct developmental pattern of gene expression is followed. This separation is achieved through the activity of 11β-hydroxy-steroid dehydrogenase type 2 located in the placenta. This enzyme converts active glucocorticoids to inactive forms, and hence acts as a gatekeeper, preventing glucocorticoids from the maternal circulation from flooding the fetal system.
Activity of the enzyme may be reduced in placentas from mothers that are on protein-restricted diets, possibly allowing increased trans-placental passage of glucocorticoids.
A reduction in placental 11β -hydroxy-steroid dehydrogenase type 2 (11βHSD2) is observed in human pregnancies and complicated by intrauterine growth restriction, suggesting a physiological importance to altered glucocorticoid exposure in the fetal programming of adult disease.
The synthetic glucocorticoid dexamethasone is a poor substrate for 11βHSD2, and crosses the placenta freely. Treatment of pregnant models with dexamethasone induces hypertension in the resulting offspring (Glucocorticoid exposure in utero: A new model for adult hypertension, 1993). This finding has led to the proposal that fetal exposure to abnormally high levels of glucocorticoids may play a key role in the programming of cardiovascular disease.
In experimental studies, whereby exposure to exogenous glucocorticoids serves as the fetal insult, a reduction in nephron number, vascular dysfunction, alterations in the renin–angiotensin system (RAS), programming of the hypothalamic–pituitary–adrenal (HPA) axis (HPA axis programming by maternal undernutrition in the male rat offspring, 2007) and hypertension are observed in the offspring.
In mature models glucocorticoids stimulate the entry of Ca into vascular smooth muscle cells, promoting vasoconstriction and increases in peripheral resistance. Glucocorticoids may also act indirectly on blood pressure. The renin–angiotensin system, in particular, is subject to regulation by corticosteroids at several levels.
Kidney
The fetal kidney appears to be extremely vulnerable to the effects of growth retardation. Studies of growth-retarded human infants indicate that the kidneys are disproportionately affected relative to the other organs. In particular, several experimental studies demonstrated that in stillborn infants growth retardation reduced the renal reserve, or number of functional nephrons in the kidneys (Relationships between glomerular filtration rate and kidney volume in low-birth-weight neonates, 2012). Nephron number, which is established before birth, is a highly variable factor in human subjects, with a range from 300 000 to 1 × 10^6 per kidney. That reduced renal reserve established in fetal life could promote an irreversible progression towards renal dysfunction and hypertension.
Kidneys with lower nephron numbers maintain their haemodynamic and excretory functions through increases in local vascular resistance and blood pressure. Increased pressures within nephrons will lead to a progressive deterioration and loss of nephrons. The subsequent rise in pressure necessary to maintain function will then promote further nephron loss and hence a vicious cycle of rising pressure and advancing renal failure is established. Ultimately, the increases in single nephron pressure and vascular resistance will translate into elevated systemic blood pressure.
Offspring of severely protein-restricted mothers had kidneys that contained fewer glomeruli than normal and this nephron deficit has been proposed to play a causal role in prenatally programmed hypertension (Relationships between glomerular filtration rate and kidney volume in low-birth-weight neonates, 2012). The changes in nephron number paralleled changes in blood pressure: hypertension was present in the models with decreased nephron number and not in those with a normal number of nephrons. Additionally, the association of reduced nephron number and increased blood pressure also suggests that a reduction in nephron number may lead to a subsequent decrease in renal excretory function, therefore, contributing to the fetal programming of hypertension. This supports a role for reduced nephron number in causing hypertension.
Other changes were observed in the kidney, as expression of the apical Na transporters along the nephron segments which shown that the expression of two transporter proteins, the thick ascending limb Na-K-2Cl co-transporter and the distal convoluted tubule Na-Cl co-transporter are increased than in control levels; no changes, instead, were seen in the expression of NHE3 or ENaC subunits (Up-regulation of renal BSC1 and TSC in prenatally pro- grammed hypertension, 2002). In few cases are reported increased Na-K-ATPase expression in whole kidney, also consistent with increased Na transport (The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero, 2001).
Increased plasma aldosterone concentration are described in some models in the prehypertensive stage, and decreased expression of the 11βHSD2 enzyme, which normally protects the mineralocorticoid receptor from stimulation by glucocorticoids (Prenatal programming of adult hypertension in the rat, 2001). These findings may indicate upregulated Na transport in the distal convoluted tubule or the collecting duct via inappropriate mineralocorticoid receptor activation.
The renin-angiotensin system
The components of the renin–angiotensin system are key elements of blood-pressure control systems. At the systemic level, and also at the level of most major organ systems, the generation of the vasoconstrictor hormone angiotensin II results in increased vascular resistance and elevation of blood pressure. Within the kidney, for example, this process allows increases in the perfusion pressures across glomeruli in order to maintain the glomerular filtration rate and haemodynamic function. Studies of the renin–angiotensin system in models are suggestive of disturbances associated with prenatal undernutrition (The role of the RAS in programming of adult hypertension, 2004). Adult models exposed to undernutrition in utero tend to have elevated concentrations of angiotensin II in the circulation, but this effect of fetal undernutrition is not statistically significant or consistent. Some studies demonstrate that, by using the inhibitor of the renin–angiotensin system, the relative hypertension induced by fetal exposure to an undernutrition could be successfully treated (Placental insufficiency results in temporal alterations in the renin angiotensin system in male hypertensive growth restricted offspring, 2007). Mature adult models exposed to undernutrition in utero showed lowered blood pressure during 1 week of renin-angiotensin system inhibitor treatment, and on withdrawal of the drug their blood pressures increased back to pretreatment levels. Studies of the effects of angiotensin converting enzyme inhibitors on programmed hypertension were broadly supportive of a role for the renin–angiotensin system in the programming mechanism linking an imbalance of maternal nutrition to later cardiovascular disease.
As said before, the RAS (renin-angiotensin system) is regulatory system strongly involved in cardiovascular and blood pressure regulation. Alterations in the RAS, induced in response to fetal insult, may serve as a potential mechanism critical to the fetal programming of hypertension.
Blockade of the RAS during the nephrogenic period leads to a marked reduction in nephron number associated with hypertension in adulthood (The role of the RAS in programming of adult hypertension, 2004). Suppression of the RAS is also observed at birth in models of fetal programming induced by gestational protein restriction and placental insufficiency. These findings support the hypothesis that moderate maternal dietary protein restriction during pregnancy results in reduced birth weight and suppression of the newborn intrarenal RAS, followed by a decreased number of glomeruli, decreased renal function (GFR/kidney weight), and consequent hypertension later in life.
Sympathetic nervous system
In humans, sympathetic activation is observed in low birth weight individuals. Increased circulating catecholamines are also reported in numerous models of fetal programming induced by placental insufficiency as well as gestational protein restriction (Catecholamines in experimentally growth-retarded rat fetus, 1991). The renal nerves play a critical role in the etiology of hypertension programmed by placental insufficiency. Renal denervation delays the development of hypertension in prepubertal offspring and abolishes hypertension in adult male IUGR (intrauterine growth restriction) offspring, suggesting a critical role for the renal nerves in the etiology of fetal-programmed hypertension (Renal denervation abolishes hypertension in low- birth-weight offspring from pregnant rats with reduced uterine perfusion, 2005).
Vascular and cardiovascular development
Impaired vascular function is observed in clinical studies including healthy children with low birth weight, suggesting that vascular consequences of fetal programming may precede the development of adult cardiovascular disease (Impaired endothelial function and increased carotid stiffness in 9-year-old children with low birthweight, 2000). In models of fetal programming, fetal insult by nutritional restriction, placental insufficiency or hypoxia, lead to vascular dysfunction associated with impaired endothelium-dependent NO availability (Reduced endothelial vascular relaxation in growth-restricted offspring of pregnant rats with reduced uterine perfusion, 2003). Enhanced responsiveness to angiotensin II is observed and suggests a causative role for the renin-angiotensin system in the vascular dysfunction programmed by fetal insult. Therefore, an imbalance in potent vasoactive factors produced by endothelial cells may contribute to impaired vascular function, leading to an increase in total peripheral resistance and contributing to the development of hypertension programmed in response to fetal insult.
The restriction of fetal substrate supply during development resulted in ultrastructural changes in left ventricular cardiac tissue. Furthermore, the changes in cardiac structure observed in all instances correlated functionally with diastolic dysfunction consistent with increased left ventricular stiffness and with increased sensitivity to ischemia/reperfusion injury (Fetal exposure to a maternal low-protein diet is associated with altered left ventricular pressure response to ischaemia-reperfusion injury, 2007). Alterations in cardiovascular development and cardiomyocyte cell cycle are observed in animal models of fetal programming induced by placental insufficiency, chronic hypoxia and nutrient restriction. Epidemiologic studies have linked intrauterine growth restriction (IUGR) with an increased incidence of cardiovascular disease later in life; reduced cardiomyocyte number in IUGR hearts may underlie such prenatal programming. Intrauterine growth restriction as a result of maternal protein restriction leads to a reduction in the number of cardiomyocytes per heart (Effect of intrauterine growth restriction on the number of cardiomyocytes in rat hearts, 2005). As cardiomyocyte proliferation is rare after birth, it is plausible that this reduction in cardiomyocytes may lead to compromised cardiac function later in life.
Oxidative stress
Oxidative stress has long been associated with hypertension and cardiovascular disease, and recent experimental studies strongly support the hypothesis that accumulation of reactive oxygen species in the kidney is, in fact, a cause of hypertension. Oxidative stress may be increased in prenatally programmed hypertension, but its pathogenetic role is largely unexplored.
Treatment with the superoxide dismutase mimetic or lipid peroxidase inhibitor abolishes hypertension that is prenatally programmed in response to maternal protein undernutrition (Oxygen radicals in cardiovascular-renal disease, 2002). Recent results have demonstrated increased nitrotyrosine content in kidneys preceding the onset of hypertension.
Twin models
Twin pregnancy represents a natural model of pregnancy nutrient restriction, which is a result of limited maternal/placental supply. Experimental studies show that there are marked differences in arterial blood values between twin and singleton. Twins demonstrate significantly increased plasma sodium, although with similar plasma osmolality and potassium and chloride concentrations as singleton. Twin and singleton hematocrit, arterial pH, and arterial carbon dioxide tension are similar, although there is a statistically, not clinically, significant difference in arterial oxygen tension. Twin systolic, diastolic, and mean arterial pressures are greater than singleton values; there is no difference in heart rate. Among urinary values, twins demonstrate reduced GFR, urine osmolality, osmolar excretion, and osmolar clearance compare with singleton. Same studies demonstrate that twins evidence marked arterial hypertension, plasma hypernatremia, and reduced GFR, which suggests a programmed syndrome of hypernatremic hypertension (Programmed syndrome of hypernatriemic hypertension in ovine twin lambs, 2005). These findings suggest that programmed sodium homeostatic mechanisms may contribute to sodium-dependent hypertension, as twins demonstrate elevated plasma sodium concentrations compared with singleton. Despite the relative hypernatremia, there is no significant difference in plasma osmolality, which suggests that levels of unmeasured plasma osmolytes are lower in twin than singleton. Importantly, twin plasma hypernatremia is not due to basal hypohydration, because it persisted throughout the intravenous hypotonic saline solution infusion.
Conclusion
Experimental studies of nutritional programming using animal models provide strong support for the hypothesis defined above. It seems clear that any major imbalance of nutrients within the maternal diet may set in train fetal adaptations, and that the occurrence of such adaptations during critical periods of development results in permanent modification of physiology and metabolism.
In summary, very early exposure to nutrient imbalance may produce embryonic adaptations which will later impact on the growth trajectory of the fetus. Later undernutrition appears to result in the down regulation of 11βHSD in the placenta. This process is a central event in programming, with an impact on many fetal organ systems. The overexposure of fetal tissues to glucocorticoids would be expected to produce growth retardation. Renal adaptation to the growth retarding effects of steroids would appear to involve a reduction in the renal reserve, which in the older model will lead to elevated systemic blood pressure and earlier renal failure.
A second consequence of fetal glucocorticoid exposure appears to be an early-life hypersensitivity to glucocorticoid action and altered regulation of the hypothalamic–pituitary– adrenal axis. Even if only transient, this effect is sufficient to activate the renin–angiotensin system. Consequent elevation of blood pressure in early postnatal life may then be reinforced by structural changes within the arteries. Work with the animal model indicates that animals exposed to low-protein diets in utero exhibit vascular smooth muscle cell hypertrophy and reduced elastin content as early as the age of weaning.
