Prenatal Programming of Hypertension

As discussed elsewhere in this issue, beginning with David Barker’s insight and original observations leading to the Fetal Origins of Adult Disease hypothesis (1), epidemiologic studies have strongly suggested that an adverse intrauterine environment may lead to adult hypertension (2–5). However, not all reports have been able to document such an association (6), and the epidemiologic studies have been criticized on the basis that it may be impossible to account for all confounding variables (7). Moreover, human epidemiology does not provide cause–effect relationships. Therefore, experimental models serve two purposes. First, they should determine unequivocally, by eliminating the variation in genetic background and other risk factors, whether prenatal factors are capable of programming adult hypertension (“proof of principle”) and, if so, whether the characteristics of the hypertension are consistent with the experience in humans. Second, they are the key to unraveling the mechanisms involved. In this review, we discuss studies on animal models of prenatally programmed hypertension as they pertain to these two objectives. In the process, we incorporate published studies selectively to serve the goals of this discussion, and we apologize to the many investigators in the field whose work is not quoted. Is Adult Hypertension Programmable in Experimental Animals by the Prenatal Environment? (“Proof of Principle”) Experimental Species It has been shown convincingly that a variety of nutritional manipulations or other variations in prenatal environment during pregnancy can program later-life hypertension in sheep, rats, pigs, and guinea pigs (8–20). The largest body of information has been gathered from rats and sheep, two species with very different lengths of gestation, maturity state of the newborn, and adult characteristics, strengthening the argument that the programming is not species specific. Nature of Prenatal Insult Because the original human reports linked prenatally programmed hypertension to intrauterine growth restriction, most experimental protocols have aimed at duplicating the fetal growth impairment. The prenatal manipulations used can generally be divided into three categories: (1) Maternal nutritional deficiencies; these have entailed 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; (2) maternal glucocorticoid treatment; and (3) interference with placental function. Maternal Diet. Global Food Restriction. Woodall and colleagues (17,18) reported that allowing rats only 30% of a normal food intake throughout pregnancy programmed the offspring for hypertension. We have shown that an even more modest 20 to 30% reduction in maternal food intake during the latter part of pregnancy is effective in inducing hypertension in the offspring (21). In contrast, others have reported that a 50% reduction in food intake during the second half of pregnancy did not cause hypertension in female rat offspring (22); the reason for the discrepancy is not clear. In the sheep, a 15% reduction in maternal food intake during the first half of gestation caused an increase of approximately 10 mmHg in mean arterial pressure in the offspring at 80 to 85 d of age (23). Thus, global food restriction for all or part of gestation can lead to increased BP 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. Protein Restriction. Reduction of maternal protein intake while maintaining a normal total caloric intake has been used extensively in the rat. “Normal” dietary protein level has usually been set at approximately 19% protein (21% casein), and the restricted levels have ranged from 12% (“mild”) to 9% (“modest”) to 5% (6% casein, “severe”) of total caloric intake. All three levels of restriction during pregnancy have been reported to increase offspring arterial pressure in adulthood, although the effects are generally greater with more severe restriction (12,16,19,20). In the pig, maternal protein reduction from the normal 14 to 0.5 to 1.0% resulted in a 10- to 25-mmHg increase in mean arterial pressure of the adult offspring (8). Furthermore, in most low-protein rat models, a normal protein diet has been provided after birth. This design may model the situation of a suboptimal fetal environment followed by an adequate postnatal environment. It may also model the phenomenon of catch-up growth (accelerated increase in body mass index in childhood), which in humans is predictive of adult hypertension independent of a reduced birth weight effect (24). Manipulation of Other Maternal Dietary Factors. Only a few studies have considered the effects of other nutrients. In one study, a low-protein diet that contained more fat and starch led to increased systolic BP in offspring compared with its own control diet, whereas a low-protein diet that contained more sugar failed to program for hypertension compared with its own control diet (25). Thus, differences in the nutrient(s) (carbohydrate and/or fat) used to make up the protein deficit in the low-protein diet in different rat models can also confound interpretation of experimental findings. Recently, increased maternal dietary fat intake (26), high (27) or low sodium (28) intake, iron deficiency (29), and water deprivation (30) during pregnancy have been reported to program offspring hypertension. Thus, the picture is emerging that the hypertension-inducing capability is not unique to any specific maternal dietary manipulation. This is perhaps not surprising considering that a specific maternal nutrient deficiency may not result in a similar deficiency in the fetus, which is well equipped to “extract” nutrients even from a deprived mother. Maternal Glucocorticoid Treatment. Because fetal programming associated with maternal undernutrition and intrauterine growth restriction (IUGR) has been proposed to involve fetal overexposure to maternal glucocorticoids, the effects of exogenous glucocorticoid administration to pregnant mothers have been studied by several investigators. Dodic and co-workers (11,31–33) reported extensively on a sheep model. Remarkably, in their hands, a dexamethasone or cortisol infusion for only 48 h between 22 and 29 d of gestation (term approximately 150 d) programs the offspring to become hypertensive. In the rat, administration of dexamethasone to the mother either throughout or during the last part of gestation causes hypertension in the adult offspring (9,21); however, this may not be a direct glucocorticoid effect (see below). Impairment of Placental Perfusion or Function. In addition to exposing the pregnant mother to the experimental conditions described above, offspring hypertension has been induced by manipulations of the uterus or the placenta. For example, in the rat, clips placed around the abdominal aorta and both uterine arteries at day 14 of gestation produced growth-retarded pups that were hypertensive as juveniles and in adulthood (34). Unilateral uterine artery ligation midway through pregnancy in the guinea pig also led to increased mean arterial pressure in the most severely growth-restricted group of offspring later in life (15). In the sheep, IUGR and postnatal hypertension have been induced by surgical removal of most of the uterine caruncles (the implantation for the In contrast, reduction of placental by of after d of gestation (term d) in sheep induced but postnatal BP in the offspring low high The of hypertension may by to the of the (see or to the that the offspring were not followed to of Prenatal key of the Fetal Origins of Adult Disease hypothesis is that the during a of that for different the and of an In the rat, we have shown that maternal dietary protein or restriction programs the and female offspring for hypertension either throughout or only during the last half of gestation but has effect on offspring adult BP only during the first half of pregnancy In contrast, reported that a 9% diet programmed hypertension in offspring whether to pregnant rats during the or although the largest effect in offspring that were throughout reported that a 9% diet to pregnant rats for only the first d of pregnancy to program the but not the female offspring for increased systolic BP The for the between the studies are not clear. In any in hands, to maternal protein restriction during the latter half of rat pregnancy to program the offspring for hypertension. to the of gestation, the in sheep to from that in the rat. reduction in maternal food intake in the first half of sheep pregnancy to an mean arterial pressure approximately 10 in postnatal life (23). The of Dodic maternal glucocorticoid have the window of in of dexamethasone to pregnant for d during the first but not the second causes hypertension in the and adult Thus, the for programming of hypertension to be in gestation in the sheep in the rat. are more at birth rats, and the in the two species may of of a specific In the for programming of hypertension with the window of the of to programming is important for design and interpretation of studies as discussed In the rat, a reduction of food intake throughout pregnancy or to protein diet induced a similar of hypertension in and female Other however, have described a 30% reduction in food intake from to d of rat gestation produced hypertension in the offspring that and more in in female rats In female rat offspring of mothers that were an protein diet throughout pregnancy were not hypertensive compared with offspring of mothers on the diet, but their mean arterial BP that were in approximately 10 two factors account for the these First, different were used to studies have used the whereas the studies that reported differences used more direct an and more food or protein restriction more modest in the studies that reported a in that a modest maternal protein restriction throughout pregnancy causes increased mean arterial pressure in but not in female offspring, whereas a more severe maternal protein restriction in hypertension in both and female offspring We have also that a high maternal sodium intake in pregnancy and to hypertension in but not in female offspring, whereas a very high maternal sodium intake programs both and female offspring for increased BP Thus, female rat offspring may be from the hypertensive effect of maternal dietary but if the maternal is severe both are However, whether this to all species and other of prenatal is not clear of Disease in and Because the of BP very in life is the age of of hypertension in many experimental models is not well the mechanisms that lead to hypertension have their in prenatal the offspring may not be hypertensive. In the rat low-protein models, hypertension has been at or around the time of and is well in by of age Fetal BP has been in the sheep models and to be or even in pregnancy that the offspring are hypertensive by of age It is that human studies have shown a not between BP and birth weight whereas have been in prenatally programmed hypertension to and to with age a that has also been described in humans with low birth weight In both rat and sheep models only to approximately to increase in systolic pressure in compared with the more severe hypertension in genetic models such as the hypertensive rat used by to BP variations in rat offspring of Hypertension only during the at and the suggested that high that were during by others the more may be to during the of the However, we have mean pressure in that are and to the is if not hypertension is In the rat, an has been the of prenatally programmed hypertension to postnatal postnatal and diet after even only for a to to have a and effect on the of hypertension diet to the hypertension The mechanisms to be The of these after of that the postnatal effect is not through a in the of Because rats are very compared for sheep and human the postnatal window may be species specific. few studies have followed the experimental to determine the In the rat with hypertension induced by maternal low-protein diet, we a reduced compared with in control rats The cause of in these However, it did not to be or that may with age It is that of BP by but did not the that factors to BP in The human observations linked low birth weight to later hypertension and IUGR has been described in many of the experimental models, whether induced by maternal dietary maternal glucocorticoid or surgical of to the However, maternal glucocorticoid in the rat and sheep to program hypertension fetal growth and IUGR does not result in adult hypertension Thus, IUGR and later hypertension can be that the programming is not by IUGR The and in addition to has been linked to low birth weight in humans (1), and it is of to its in animal and even in the offspring have been induced by prenatal with or IUGR mechanisms may of of that may and of the glucocorticoid In contrast, reported that sheep that were hypertensive by prenatal administration of dexamethasone The and or is at the time of the of this However, it is that hypertension is the result of Adult in rat models of prenatally programmed hypertension that is induced by maternal restriction but not in in which hypertension is induced by protein restriction or in rats and sheep after prenatal in have been described in models, but the of has between studies or in body increased body have also been reported In IUGR and most of the can be induced by prenatal manipulations in experimental but these can also be from the of hypertension. of BP Maternal and Placental The of the from mother to that is for fetal programming has not been investigators have proposed that the key is increased fetal to caused by maternal glucocorticoid levels a result of by increased of to the fetus, or by of the fetal Fetal levels have been reported to be increased by maternal food restriction but not by maternal protein restriction of a glucocorticoid that is not by the (see to pregnant rats or sheep on normal diet to hypertension in the offspring the However, in the rat reduced maternal food intake may have a In hands, dexamethasone food control pregnant were with rat all offspring that the hypertensive effect of dexamethasone in the rat may be an one (21). The studies by Dodic in the sheep, however, are to involve nutritional deprivation of the of the and that the offspring were not growth-restricted at birth. The is from to maternal by the placental which the glucocorticoid in humans and sheep, in to an of the may be reduced in from rats that are on allowing increased of administration of an of to pregnant rats reported to program for hypertension in their offspring but these not be in a that used a but of the discrepancy may be to other effects of high of the information is on other such as other and growth factors that may in the programming of the of in the and have been described in in many experimental models of prenatal Only that have been proposed to be in BP programming are discussed and Glucocorticoid is that the prenatal environment may program the in in glucocorticoids, glucocorticoid other and in later life The of the in prenatally programmed however, is In the sheep, both maternal restriction and administration may in the offspring restriction in pregnancy has been reported to the during fetal life to increase glucocorticoid in several of the and to result in cortisol in later life (23). Dodic and co-workers the in the model. they in the glucocorticoid in the fetus, the did not in the postnatal and the offspring in either or cortisol levels leading the to that programming of hypertension is not by the have also been reported in rat models of hypertension programmed by prenatal protein restriction or and increased (the as well as normal to have been of the glucocorticoid has been reported in and in both fetal and adult life in the rat with prenatally programmed hypertension whereas in the in one In in can be in models of prenatally programmed but they not to with the of on a direct of the in the of hypertension. This is by the that in models, the prenatal has not induced hypertension similar in the in the offspring of of the glucocorticoid to the of hypertension has not been and Function. has been either in as the BP to or or in to or in to a variety of In the rat hypertension models induced by maternal dietary to be whereas to have been reported offspring that are hypertensive by prenatal food restriction or glucocorticoid administration to have a normal to Because most of hypertension and may be of these be as of in prenatally programmed hypertension. Moreover, prenatal manipulations have resulted in similar or in hypertension level in to has been described in rat offspring at of age after of the fetal by the in to BP has been reported in rats and sheep and the has been that low BP during prenatal life may result in of control and to the later of hypertension However, at in sheep, the can be from dexamethasone programs hypertension whereas later in hypertension information is on in prenatally programmed hypertension. and increased has been reported in the rat, whereas were in sheep of the in the does not to be increased in either species We an increase in in a rat model but the of this is not in be by deficiency in the this is discussed and The of the in the of hypertension is a body of experimental In human in has been reported to be increased studies have the state of in experimental prenatally programmed with prenatal and of the may of the during life to be In later both and increased has been In study, we a from low to high in the rat, but the only after hypertension and were during the on the of in the of the hypertension. on the basis of their studies in sheep that the does not a in the hypertension induced by prenatal has been described in the rat but its The has In their model of prenatal dexamethasone administration in sheep, Dodic reported increased of in and in in and of the to in adult in by the prenatal cortisol resulted in in the fetus, but the did not after birth In rat hypertension programmed by a prenatal low-protein diet, increased in the and and the hypertension by direct infusion of or This a of the can be The of the is discussed of the two most extensively studied rat and sheep, that the window of to BP programming to with the of in during the second half of pregnancy in the rat and during the first in the sheep that may be involved. were the first to the hypothesis that any hypertension the of the in the the of the may be a of all hypertension and has been in most of experimental hypertension experience of prenatally programmed hypertension is consistent with pressure As discussed is information to a of the in prenatally programmed hypertension. of In first reported that rat offspring of severely mothers that contained This has been more by several and a deficit has been proposed to a in prenatally programmed hypertension The for the total of have of as well as of in The used of the time and is of by such as the and the of one of the has the effect of different of protein restriction on the of and on in the rat The are in It that the severe of maternal protein restriction used by causes a reduction of to in the of in the offspring This effect is in both and female rats but to be greater in modest protein restriction also in a in in rats, although to a protein maternal diet the total by in offspring The of the total of all not different from that in normal consistent with in to a reduction in In contrast, female offspring of these mothers a normal of that were of normal Thus, of and only a modest protein restriction a in programming of the in in Hypertension in the with and not in with a normal of This a for reduced in hypertension. The of a by modest protein restriction in the rat, are in with information is in other models and has been described in rats that were hypertensive by prenatal dexamethasone administration in pigs after prenatal protein restriction and in sheep after prenatal dexamethasone In the last study, however, the offspring were studied at of the between deficit and is experimental to the hypothesis that reduced is for later hypertension. In normal rats, on the first day of postnatal life causes hypertension as as of and this the of which did at in rats in sheep this during the of in the to increased mean arterial at and of age studies have used for in the rat low-protein model reduced by to in both and female offspring of severely to body weight reduced in offspring and also to be reduced in female severe protein restriction, in female offspring did not but reduced by approximately in offspring compared with This did not but this is at the of of the and a of this be In a of only in with a of in that is increased in these compared with a that may have important for the of in the rat model of prenatally programmed hypertension has been reported by others as well However, in models, hypertension to a in offspring that were hypertensive by prenatal dexamethasone a reduced of Moreover, hypertension induced by placental in the rat did not result in at of age and studies by one of the have shown normal and in rats that were hypertensive by high maternal dietary sodium Thus, although the hypertension has been suggested to result from as a result of reduced and the may be more and involve other mechanisms Furthermore, the mechanisms of programming for hypertension may not be in different We have the that a in the of is by of by the experimental for increased is in that has not been in any in prenatally programmed hypertension. we have the of the the rat and shown that the of two the and the are increased to and of control during the by an increase in their levels were in the of or however, studies of these by other for by of the between the and the reported increased in rat at of also consistent with increased We have described increased in the rat in the and of the which the from by glucocorticoids, has been reported in the rat and may in the or the but more direct is The of the in has is to be important in normal and variations in dietary protein can the In the rat low-protein we have shown that protein and protein and and levels are reduced in the and offspring compared with Furthermore, of these offspring the normal of and were hypertensive in We also that of the with in normal rats for the first d after birth (the latter of in the led to a reduced of and hypertension in adulthood Thus, to be a the during and adult hypertension. the hypothesis that maternal protein restriction programs the offspring for hypertension by the during leading to a reduced and hypertension later in The may also in the of the offspring hypertension in postnatal The of the in BP control is experimental that of the the independent of the state of the may and hypertension that the is in the in prenatally programmed hypertension in the rat, control levels during the in or In sheep that have been programmed to become hypertensive by maternal glucocorticoid or by maternal food restriction of has been in gestation and at perhaps the more state of the are consistent with of and a for the in the of prenatally programmed hypertension. The effect of may be by a of the However, most of the described in the were and more work is to a for the in the of the hypertension. the of the is an important to their and has been associated with and experimental studies strongly the hypothesis that of species in the in a cause of hypertension may be increased in prenatally programmed hypertension but its is have increased of in the of hypertension. we were able to the of hypertension and by administration of the species to the rats As a of we an increased of in the and of the has effects similar to of in other of experimental hypertension and that in the may be part of a and is a of to convincingly that adult hypertension is by the prenatal environment in a variety of It is also from the that the picture of prenatal programming is from In it is to the of such as specific dietary and BP as well as all of which may the the information is to into a and it may become in to to different mechanisms for hypertension programmed by different prenatal However, is that investigators are different of the been able to their around the The that the is programmed to nutrients in later life may to as Because dietary has been throughout the human for the last two we most experimental may be well equipped to but to and hypertension. Prenatal conditions that the fetus, for or may program a of the mechanisms as a perhaps the of several This programming of be in postnatal life with dietary in hypertension. Because the of the important in the one of the that is to causes of from a increased in the and the in very is of the during of the of growth factors that in normal are also for the The emerging field of is also up is programmed in the fetus, it is the result of is that of through of be the of prenatal programming of the is the for in other prenatally programmed be on to the as a result of of the of prenatally programmed hypertension with rat offspring of mothers that were to low protein diet during the second half of pregnancy; control the control and in adult offspring of rats that were normal protein or low protein or 5% diets throughout pregnancy or during the last half of pregnancy the in from and by in of offspring from maternal low-protein (6% at of as of of control and of the control of prenatally programmed hypertension by postnatal with species or offspring from control offspring from low-protein (6% postnatal treatment; offspring from low-protein offspring from low-protein The were from to of BP are at of all other in by of and by from the of of in by of and and a from the