This Article Abstract Full Text (PDF) All Versions of this Article: 41/3/457    most recent 01.HYP.0000053448.95913.3Dv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alexander, B. T. Search for Related Content PubMed PubMed Citation Articles by Alexander, B. T.

(Hypertension. 2003;41:457.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Placental Insufficiency Leads to Development of Hypertension in Growth-Restricted Offspring

Barbara T. Alexander

From the Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson.

Correspondence to Barbara T. Alexander, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505. E-mail balexander{at}physiology.umsmed.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Low birth weight is a suggested risk factor for the development of hypertension. The purpose of the present study was to determine whether a model of intrauterine growth restriction produced in response to placental insufficiency in the pregnant rat was associated with marked elevations in blood pressure. Reduced uterine perfusion initiated in late gestation resulted in low-birth-weight offspring (5.8±0.1 versus 6.6±0.2 g, P<0.05, growth-restricted versus control, respectively). Mean arterial pressure, as measured in conscious, chronically instrumented rats, was significantly elevated as early as 4 weeks of age (113±3 versus 98±2 mm Hg, P<0.05) and was associated with significant decreases in body weight (66±2 versus 81±3 g, P<0.05) in growth-restricted (n=15) versus control (n=15) rats. Marked elevations in arterial pressure at 8 weeks of age (male: 133±3 versus 121±6 mm Hg, P<0.05; female: 137±4 versus 112±6 mm Hg, P<0.01) were associated with sex-specific decreases in body weight (male: 251±6 versus 275±10 g, P<0.05; female: 163±6 versus 180±6 g) in male growth-restricted (n=12) versus male control (n=9) rats and in female growth-restricted (n=8) versus female control (n=7) rats. At 12 weeks of age, hypertensive (144±4 versus 131±3 mm Hg, P<0.05) male growth-restricted offspring (n=10) had no alterations in glomerular filtration rate (2.3±0.3 versus 2.2±0.2 mL/min) compared with control (n=10) offspring; even when adjusted for kidney weight (1.7±0.3 versus 1.5±0.3 mL · min^-1 · g^-1 kidney), despite marked decreases in body weight (305±9 versus 343±10 g, P<0.05). These data suggest that placental insufficiency induced by reduced uterine perfusion in the pregnant rat results in low-birth-weight offspring predisposed to development of hypertension.

Key Words: hypertension, experimental • kidney • rat • arterial pressure • glomerular filtration rate

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Hypertension is a multifactorial disorder that is thought to result from both genetic and environmental factor interactions. Numerous epidemiological studies have reported an association between low birth weight (LBW) and the risk of hypertension.^1,2 This association has been reported in a variety of populations from around the world and is further supported because elevations in blood pressure are also found in LBW children.^3–6 Thus, the inverse relationship between LBW and hypertension suggests that factors present in the prenatal environment that affect fetal growth are responsible for the in utero programming of arterial blood pressure control.^7–9

Nutrient and oxygen supply limitations are the components of the intrauterine environment that limit fetal growth and result in small-for-gestational-age newborns. Animal models of fetal malnutrition induced by maternal nutrition restriction support a role for programming of hypertension owing to an adverse fetal environment.^10–12 Woods et al¹³ report that protein restriction during the last third of gestation in the rat results in offspring with reduced renal function and hypertension. In the rat, nephrogenesis occurs during the last third of gestation and continues for several days after delivery.^14,15 As the kidneys are known to play an important role in the long-term regulation of arterial pressure,¹⁶ this suggests that timing of the insult in utero is critical to the development of hypertension. Thus, fetal adaptations to oxygen and nutrient restriction that occur during a critical period of fetal renal development may result in long-term effects and increased risk for development of hypertension.

In the United States, a higher percentage of LBW babies are born relative to that of other Western countries, with the highest rates of LBW localized in the southern states and, in particular, within the black population.¹⁷ The highest rates of hypertension are also concentrated in the South, with a greater prevalence of hypertension within the black population.¹⁸ As intrauterine growth restriction (IUGR) within the Western world is more likely the result of impaired uteroplacental perfusion rather than of maternal malnutrition,¹⁹ we have used a model of in vivo placental insufficiency initiated in late gestation in the rat to examine the inverse relationship between LBW and hypertension. Specifically, a chronic reduction in uteroplacental perfusion in the pregnant rat, induced by placement of a silver clip around the aorta below the renal arteries at the start of late gestation, resulted in reduced uterine perfusion by 35% to 45%²⁰ and IUGR with birth at term. Thus, the purpose of the present study was to determine whether a chronic reduction in uterine perfusion initiated in the last third of gestation in the pregnant Sprague-Dawley rat was associated with growth-restricted offspring that are predisposed to hypertension.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Animals
All experimental procedures executed in this study were in accordance with National Institutes of Health guidelines for use and care of animals, with approval of all protocols by the Animal Care and Use Committee at the University of Mississippi Medical Center. Female timed-pregnant Sprague-Dawley rats were purchased from Harlan Sprague-Dawley Inc (Indianapolis, Ind) and housed 1 to a cage in a temperature-controlled room (23°C) with a 12-hour/12-hour light/dark cycle with food and water available ad libitum.

At day 14 of gestation, rats destined for reduced uterine perfusion were clipped as described below. All dams were allowed to deliver at term, with birth weight recorded within 12 hours. At this time, a control litter was size-matched per growth-restricted (IUGR) litter, with a minimum litter size of 8 pups, with all marked for identification by tattooing (Spaulding Special electronic Tattoo Marker, Spaulding and Rogers). Pups were weighed twice a week after birth and were weaned at 3 weeks of age. Mean arterial pressure (MAP) and renal hemodynamics were determined in conscious, chronically instrumented rats. Offspring from different litters were chosen at random, with simultaneous measure of control and IUGR offspring. In the initial study for measure of MAP, a total of 10 reduced-uterine-perfusion dams and 10 control dams were used with the following breakdown per experiment. At 4 weeks of age, a total of 7 male and 8 female controls and 8 male and 7 female IUGR offspring were used for measure of MAP and determination of organ weights. At 8 weeks of age, a total of 9 male and 7 female controls and 12 male and 8 female IUGR offspring were used for measure of MAP. For measure of MAP and determination of organ weights at 12 weeks of age, 12 male and 8 female controls and 9 male and 8 female IUGR were used. Before instrumentation, rats in the 8- and 12-week MAP groups were used for 24-hour determination of sodium excretion and of food and water intake. In a second study for determination of renal hemodynamics in conjunction with measure of MAP, a total of 6 reduced-uterine-perfusion dams and 7 control dams were used with the following breakdown per experiment. At 8 weeks of age, 13 male control and 11 male IUGR offspring were used for determination of glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), and MAP; 10 male control and 10 male IUGR were used at 12 weeks of age. For measure of fetal weights at day 19 of gestation, 8 litters per reduced uterine perfusion and 8 per control dam were used.

Reduced Uterine Perfusion in the Pregnant Rat
Eder and McDonald²¹ have previously reported that placement of a silver clip around the aorta below the renal arteries during mid-to-late gestation in the pregnant rat results in a 35% to 45% reduction in uterine perfusion. A modification of this model, as described previously, was used to induce IUGR.²⁰ Briefly, at day 14 of gestation, rats were anesthetized with 2% isoflurane (WA Butler Co) delivered by anesthesia apparatus (Vaporizer for Forane Anesthetic, Ohio Medical Products). A silver clip (0.203-mm ID) was placed around the isolated abdominal aorta above the iliac bifurcation, with additional clips placed on both right and left branches of uterine arteries (0.100-mm ID). IUGR was not present in sham-operated control pregnant rats.

Measurement of Renal Hemodynamics and Arterial Pressure in Conscious Rats
In brief, all rats undergoing surgical procedures were anesthetized with 2% isoflurane, as described above, and were surgically instrumented with catheters in the femoral vein, carotid artery, and bladder, as previously described.²² Renal function and MAP measurements were performed in conscious, chronically instrumented rats, as described previously.²² Briefly, GFR and ERPF were calculated from radioactivity of Glofil [¹²⁵I] (sodium iothalamate, Questcor Pharmaceuticals) and concentration of para-aminohippurate, respectively, in plasma and urine. On completion of MAP determination, total body and organ (kidney, brain, liver, and heart) weights were recorded.

Statistical Analyses
GB-STAT, version 6.5, was used for all statistical analysis. All data are expressed as mean±SEM. Comparisons of control offspring with IUGR were analyzed by using factorial ANOVA followed by the Scheffé test. A value of P<0.05 was considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Effect of IUGR on Birth Weight
Birth weight was significantly decreased in offspring from pregnant rats with reduced uterine perfusion relative to offspring from control pregnant rats. Specifically, at birth IUGR were significantly smaller than their control offspring (control) counterparts (5.8±0.1 versus 6.6±0.2 g, P<0.01, IUGR versus control, respectively) (Figure 1). In addition, growth restriction induced by reduced uterine perfusion was not sex specific (5.8±0.2 versus 6.6±0.1 g, P<0.01, male IUGR versus male control, respectively; 5.7±0.1 versus 6.5±0.1 g, P<0.01, female IUGR versus female control, respectively). Marked decreases in fetal size were evident as early as day 19 of gestation (2.0±0.1 versus 2.4±0.3 g, P<0.05, IUGR versus control, respectively). In addition, a chronic reduction in uterine perfusion in the pregnant rat resulted in low-birth-weight offspring that remained smaller in size, as defined by weight in grams, relative to control offspring with increasing age (Figure 2).

View larger version (22K): [in this window] [in a new window]   Figure 1. Measure of birth weight in a rat model of IUGR induced by reduced uterine perfusion. Data shown is for IUGR versus control offspring, combined for both male and female. *P<0.01 vs control. All data are mean±SEM.

View larger version (31K): [in this window] [in a new window]   Figure 2. Growth progression in a rat model of IUGR induced by reduced uterine perfusion. Data shown is for IUGR versus control offspring, combined for both male and female, at 12 weeks of age. All data are mean±SEM.

Effect of IUGR on MAP
As early as 4 weeks of age, a significant increase in arterial pressure was evident in growth-restricted offspring compared with controls (113±3 versus 98±2 mm Hg, P<0.05, IUGR versus control, respectively) (Figure 3). However, marked elevations in MAP were not sex specific, as significant increases in arterial pressure were present at 4 weeks of age in both male (114±4 versus 97±4 mm Hg, P<0.05) and female (113±4 versus 99±2 mm Hg, P<0.05) growth-restricted offspring compared with controls, respectively (Figure 3). At 8 weeks of age, marked elevations in MAP were still apparent in the growth-restricted offspring (134±2 versus 117±4 mm Hg, P<0.01, IUGR versus control, respectively), an observation that remained non–sex specific (133±3 versus 121±6 mm Hg, P<0.05, male IUGR versus male control, respectively; 137±4 versus 112±6, P<0.01, female IUGR versus female control, respectively) (Figure 3). However, at 12 weeks of age, sex-specific differences in MAP were observed, as male growth-restricted offspring exhibited a significant increase in arterial pressure (158±1 versus 135±2 mm Hg, P<0.01), whereas female IUGR did not (139±4 versus 126±3 mm Hg; IUGR versus control, respectively) (Figure 3).

View larger version (31K): [in this window] [in a new window]   Figure 3. Measure of MAP in a rat model of IUGR induced by reduced uterine perfusion. Data shown is for both male and female IUGR versus control offspring, at 4, 8, and 12 weeks of age. *P<0.05 vs male control; P<0.05 vs female control; P<0.01 vs control; and P<0.01 vs control. All data are mean±SEM.

Effect of IUGR on Body Weight
At 4 weeks of age, marked increases in arterial pressure were associated with significant decreases in body weight in both male (65±2 versus 87±7 g, P<0.05) and female (68±3 versus 76±1 g, P<0.05) growth-restricted offspring relative to control, respectively. At 8 weeks of age, hypertensive male growth-restricted offspring retained a marked decrease in body weight relative to control (251±6 versus 275±10 g, P<0.05, IUGR versus control, respectively). However, hypertensive female growth-restricted offspring at 8 weeks of age exhibited a nonsignificant decrease in body weight (163±6 versus 180±6 g, IUGR versus control, respectively). A marked reduction in body weight was still evident at 12 weeks of age in the hypertensive male growth-restricted offspring (307±9 versus 348±11 g, P<0.05, IUGR versus control, respectively). Despite the significant difference in body weight, 24-hour food and water intake did not differ at either 8 or 12 weeks of age, even with adjustment for body weight (data not shown).

Effect of IUGR on Renal Function
As arterial pressure was significantly elevated in growth-restricted offspring compared with control offspring, additional animals were examined for measure of renal hemodynamic parameters. Marked elevations in arterial pressure were again consistently observed in male IUGR offspring at both 8 (142±4 versus 127±4 mm Hg, P<0.05) and 12 (144±4 versus 131±3 mm Hg, P<0.05) weeks of age (IUGR versus control, respectively). However, the significant increase in MAP in male growth-restricted offspring was associated with nonsignificant differences in both GFR and ERPF. Specifically, neither GFR (2.1±0.3 versus 2.7±0.5 mL/min) nor GFR adjusted for kidney weight (1.7±0.3 versus 2.4±0.6 mL · min^-1 · g^-1 kidney) differed significantly at 8 weeks of age in growth-restricted offspring compared with control, respectively. ERPF (12.1±1.8 versus 10.3±1.5 mL/min) and ERPF adjusted for kidney weight (8.6±1.4 versus 8.1±1.8 mL · min^-1 · g^-1 kidney) were also not significantly altered (IUGR versus control, respectively). At 12 weeks of age neither GFR (2.3±0.3 versus 2.2±0.2 mL/min) nor ERPF (7.3±1.8 versus 8.8±1.9 mL/min) differed, even when adjusted for kidney weight (GFR: 1.7±0.3 versus 1.5±0.3 mL · min^-1 · g^-1 kidney [Figure 4]; ERPF: 5.3±0.7 versus 6.3±1.0 mL · min^-1 · g^-1 kidney) for IUGR versus control, respectively. In addition, RVR was not significantly altered at either 8 weeks of age (19.8±6.4 versus 14.9±3.1 mm Hg) or 12 weeks of age (14.3±2.4 versus 10.4±1.6 mm Hg; IUGR versus control, respectively) (Figure 4). Twenty-four–hour urinary sodium excretion in hypertensive IUGR offspring was not significantly altered compared with control offspring at either 8 (1.3±0.2 versus 1.2±0.2 mEq/d) or 12 (3.8±0.5 versus 2.4±0.6 mEq/d) weeks of age (IUGR versus control, respectively).

View larger version (25K): [in this window] [in a new window]   Figure 4. Measure of RVR and GFR adjusted to kidney weight in a rat model of IUGR induced by reduced uterine perfusion. Data shown is for male IUGR versus male control at 12 weeks of age. All data are mean±SEM.

Effect of IUGR on Organ Weights
Growth restriction induced by placental insufficiency was associated with alterations in organ weights (Table). At 4 weeks of age, brains were significantly smaller in male IUGR offspring (1.39±0.02 versus 1.45±0.01 g, P<0.05, IUGR versus control, respectively). However, the brain-to–body weight ratio was significantly increased (21.8±0.88 versus 17.1±0.80 g/kg, P<0.01; male IUGR versus male control, respectively). A similar observation was noted with both kidney weight and kidney-to–body weight ratio in the male growth-restricted offspring (kidney: 0.42±0.02 versus 0.44±0.03 g, P<0.05; kidney/body weight: 6.49±0.25 versus 5.17±0.25 g/kg, P<0.05; male IUGR versus male control, respectively). In addition, a significant reduction in liver size was observed in male IUGR rats at 4 weeks of age (3.22±0.09 versus 4.13±0.26 grams, P<0.01; male IUGR versus male control, respectively). At 12 weeks of age, only a significant decrease in brain weight was noted in male growth-restricted offspring (1.74±0.02 versus 1.95±0.02 grams, P<0.01; male IUGR versus male control, respectively).

View this table: [in this window] [in a new window]   Organ Weights in a Rat Model of Intrauterine Growth Restriction

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Associations between LBW and later disease such as hypertension have been found in a variety of populations from around the world^1,2 and are independent of influences such as obesity and smoking, suggesting that increases in blood pressure may be linked to impaired fetal growth.^7,8 Fetal growth, regardless of its genetic component, can be constrained by its environment or fetal undernutrition.^8,23 Fetal undernutrition or availability of nutrients and oxygen is a major contributor to perinatal programming of hypertension and may result from either maternal undernutrition or inadequate delivery of nutrients to the fetus.¹⁹ Numerous investigators have shown that maternal undernutrition induced by protein restriction during gestation in the rat results in offspring that are hypertensive.^10–12 However, as a strong correlation between hypertension and LBW is found in well-nourished populations,^24,25 fetal undernutrition as a result of placental insufficiency, rather than maternal undernutrition, may be the major cause of IUGR in the Western world.¹⁹

A major goal of the present study was to determine whether a model of placental insufficiency induced in late gestation by a reduction in uterine perfusion in the pregnant rat resulted in IUGR offspring born at term that were predisposed to development of hypertension. In the present study, placental insufficiency was induced by a chronic reduction in uterine perfusion initiated at day 14 of gestation in the pregnant rat. Offspring from the reduced uterine perfusion pregnant rats had significantly lower birth weights compared with those of offspring from control pregnant rats. Specifically, birth weight was reduced by 12% in IUGR offspring compared with control. In addition, MAP, as measured by carotid arterial catheter in conscious animals, was significantly increased as early as 4 weeks of age in both male and female IUGR offspring (17 and 15 mm Hg increase, P<0.05, respectively). A significant increase in MAP was evident at 12 weeks of age in male IUGR offspring (23 mm Hg increase, P<0.05) and was associated with a marked reduction in body weight, present since birth. In female IUGR offspring, MAP was significantly elevated at 8 weeks of age (25 mm Hg increase, P<0.05), yet marked differences in body weight were no longer apparent. Thus, in the present study, significant elevations in MAP were associated with equivalent or significant decreases in body weight. Furthermore, IUGR induced in this model of placental insufficiency was associated with sex-specific differences, as at 12 weeks of age, male IUGR offspring maintained a significant elevation in MAP, whereas female IUGR offspring had a nonsignificant elevation. Sexual dimorphism is also apparent in the protein restriction model of fetal undernutrition as male offspring of modest protein-restricted dams are hypertensive,^10,13 whereas both male and female offspring are hypertensive under conditions of more severe protein restriction during gestation.^11,13

The kidneys are known to play a major role in the long-term regulation of arterial pressure through pressure natriuresis, whereby changes in renal perfusion pressure lead to alterations in sodium and water balance.¹⁶ Support for a key role of the kidneys in the association of fetal undernutrition and the intrauterine programming of hypertension is suggested from studies of fetal undernutrition, induced by maternal protein restriction during pregnancy in the rat, in which importance of the timing of the insult is noted.^12,13 Specifically, investigators found that protein restriction administered during the first third of gestation only resulted in offspring with normal renal morphology.^12,13 However, protein restriction encompassing late gestation, during the period of nephrogenesis, resulted in hypertensive offspring that exhibited a significant decrease in glomerular or nephron number^10–13 and kidney-to–body weight ratio.^11,12 Alterations in renal structure in the rat, as induced by placental insufficiency, have been noted, as partial uterine artery ligation initiated at day 17 resulted in a 30% reduction in nephron number together with a significant reduction in kidney weight in 2-week-old growth-restricted offspring.²⁶ Thus, models of fetal undernutrition in the rat, whether initiated in late gestation by either maternal undernutrition or placental insufficiency, are associated with a deficient in nephron number and reduced kidney weight and, therefore, evidence for impaired fetal renal development.

Fetal undernutrition is identified with 2 patterns of growth restriction. Proportionate or symmetric growth restriction, characteristic of developing countries, is generally indicative of fetal undernutrition present throughout gestation. Disproportionate or asymmetric growth restriction, a pattern more common to the Western world, is suggestive of fetal undernutrition restricted to the last third of gestation.^9,27 In our model of placental insufficiency, a pattern of asymmetric growth was present in male, but not female, IUGR offspring. Specifically, the brain-to–body weight ratio was significantly increased at 4 weeks in male IUGR offspring, supporting the brain-sparing feature of fetal programming.²⁸ However, reduced uterine perfusion initiated in late gestation resulted in reduced kidney weight at 4 weeks of age in male IUGR offspring (P<0.05). In addition, at 4 weeks of age, liver and brain weights were also significantly reduced in male IUGR offspring; at 12 weeks of age, brain weight only was markedly reduced. Maternal protein restriction has been shown to result in offspring with impaired gluconeogenesis and glucose handling.²⁸ As LBW is related to the occurrence of syndrome X, reduced liver size at 4 weeks of age in the male IUGR offspring may also contribute to the development of hypertension in these animals. In addition, as brain weights were reduced at both 4 and 12 weeks of age in the male IUGR offspring, limitations in the intrauterine environment in this model of placental insufficiency may also result in neural fetal programming, leading to the development of hypertension. Specifically, alterations in peripheral sympathetic nervous control could result in impaired renal development, as evidence suggests that the renal nerves play an important role in renal development through stimulation of the renin-angiotensin system.^29,30 Thus, asymmetric growth restriction resulting from limited growth of selective organs in late gestation, owing to alterations in nutrient supply to rapidly developing organs, may result in improper development and subsequent hypertension.

As the kidneys play an important role in the long-term control of arterial pressure, underlying renal mechanisms may be responsible for mediating the hypertension in IUGR offspring produced in response to reduced uterine perfusion. Mechanisms mediating hypertension in fetal programming may involve a decrease in GFR as a result of decreased nephron number, an increase in tubular reabsorption, or degrees of both. A significant reduction in glomerular number, as induced by gestational maternal protein restriction, is associated with a significant reduction in GFR normalized to kidney weight.¹⁰ However, although GFR and GFR normalized to kidney weight tended to be reduced at 8 weeks of age in IUGR offspring relative to control, placental insufficiency induced by reduced uterine perfusion at day 14 of gestation was not associated with significant reductions in either GFR or GFR normalized to kidney weight. In addition, 24-hour determination of sodium excretion did not differ significantly, despite a marked increase in arterial pressure in IUGR offspring. Thus, the normal regulatory systems that control pressure natriuresis may be altered in this model of LBW induced by placental insufficiency. Indeed, preliminary studies in our laboratory indicate that the pressure natriuresis relationship is altered in the hypertensive IUGR offspring. Many known regulatory mechanisms control sodium balance, and any alterations in natriuretic factors, such as NO, or antinatriuretic factors, such as the renal sympathetic nervous system and angiotensin II, in addition to alterations in physical factors, can result in abnormal pressure natriuresis, thus leading to hypertension. Further studies will be necessary to delineate the role of these regulatory systems in mediating the altered renal handling of sodium in the hypertensive IUGR offspring produced in response to placental insufficiency in the pregnant rat.

Perspectives
Fetal malnutrition, owing to an insufficient nutrient delivery via reduced uteroplacental perfusion or maternal undernutrition, limits fetal growth and results in an increased risk for development of hypertension and cardiovascular disease. The present study provides further support for an inverse relationship between birth weight and hypertension, as placental insufficiency initiated at mid-to-late gestation in the pregnant rat resulted in growth-restricted offspring predisposed to the development of hypertension. However, the marked increases in arterial pressure observed in growth-restricted offspring were not associated with significant decreases in GFR or GFR normalized to kidney weight. Thus, in this model of IUGR and hypertension, although marked elevations in arterial pressure may be mediated in part by a reduction in GFR, inappropriate tubular sodium reabsorption may also play an important role. The control of renal sodium excretion is multifactorial and involves humoral, neural, and physical mechanisms. Thus, regulatory systems such as the renin-angiotensin system, the renal sympathetic nervous system, or alterations in expression of renal sodium transporters may contribute to reduced pressure natriuresis and subsequent hypertension. Therefore, this model of IUGR will allow for examination of the underlying mechanisms that may be responsible for mediating the hypertension induced by in utero programming owing to placental insufficiency and resulting in fetal undernutrition constrained to late gestation.

	Acknowledgments

 
This work was supported American Heart Association grant 0160157B, National Institutes of Health (NIH) grants HL38499 and HL51971, and the NIH National Research Service award HL10137-01. I thank Kathy Cockrell, Christy Steijen, and Andrew Hendon for their excellent technical assistance.

Received September 3, 2002; first decision September 20, 2002; accepted December 10, 2002.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Law CM, Shiell AW. Is blood pressure inversely related to birth weight?: the strength of evidence from a systematic review of the literature. J Hypertens. 1996; 14: 935–941.[Medline] [Order article via Infotrieve]
2. Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens. 2000; 18: 815–831.[CrossRef][Medline] [Order article via Infotrieve]
3. Law CM, Shiell AW, Newsome CA, Syddall HE, Shinebourne EA, Fayers PM, Martyn CN, de Swiet M, Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age. Circulation. 2002; 105: 1088–1092.[Abstract/Free Full Text]
4. Lurbe E, Torro I, Rodriguez C, Alvarez V, Redon J. Birth weight influences blood pressure values and variability in children and adolescents. Hypertension. 2001; 38: 389–393.[Abstract/Free Full Text]
5. Yiu V, Buka S, Zurakowski D, McCormick M, Brenner B, Jabs K. Relationship between birthweight and blood pressure in childhood. Am J Kidney Dis. 1999; 33: 253–260.[Medline] [Order article via Infotrieve]
6. Eriksson J, Forsen T, Tuomilehto J, Osmond C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension. 2000; 36: 790–794.[Abstract/Free Full Text]
7. Barker DJ. The fetal origins of hypertension. J Hypertens. 1996; 14 (suppl): S117–S120.
8. Godfrey KM, Barker DJ. Fetal nutrition and adult disease. Am J Clin Nutr. 2000; 71 (suppl): S1344–S1352.[Abstract/Free Full Text]
9. Barker DJP. Mothers, Babies, and Disease in Later Life. London: BMJ Publishing Group, 1994.
10. Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R. Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatr Res. 2001; 49: 460–467.[Medline] [Order article via Infotrieve]
11. Vehaskari VM, Aviles DH, Manning J. Prenatal programming of adult hypertension in the rat. Kidney Int. 2001; 59: 238–245.[Medline] [Order article via Infotrieve]
12. Langley-Evans SC, Welham SJ, Jackson AA. Fetal exposure to a maternal protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci. 1999; 64: 965–974.[CrossRef][Medline] [Order article via Infotrieve]
13. Woods LL. Fetal origins of adult hypertension: a renal mechanism? Curr Opin Nephrol Hypertens. 2000; 9: 419–425.[CrossRef][Medline] [Order article via Infotrieve]
14. Larsson L, Aperia A, Wilton P. Effect of normal development on compensatory renal growth. Kidney Int. 1980; 18: 29–35.[Medline] [Order article via Infotrieve]
15. Gilbert T, Lelievere-Pegorier M, Malienou R, Meulemans A, Merlet-Benichou C. Effects of prenatal and postnatal exposure to gentamicin on renal differentiation in the rat. Toxicology. 1987; 43: 301–313.[CrossRef][Medline] [Order article via Infotrieve]
16. Guyton AC, Coleman TG, Cowley AV Jr, Scheel KW, Manning RD Jr, Norman RA Jr. Arterial pressure regulation: overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med. 1972; 52: 584–594.[CrossRef][Medline] [Order article via Infotrieve]
17. Hoyert DL, Freedman MA, Strobino DM, Guyer B. Annual summary of vital statistics: 2000. Pediatrics. 2001; 108: 1241–1255.[Abstract/Free Full Text]
18. Hall WD, Ferrario CM, Moore MA, Hall JE, Flack JM, Cooper W, Simmons JD, Egan BM, Lackland DT, Perry M Jr, Roccella EJ. Hypertension-related morbidity and mortality in the southeastern United States. Am J Med Sci. 1997; 313: 195–209.[CrossRef][Medline] [Order article via Infotrieve]
19. Henriksen T, Clausen T. The fetal origins hypothesis: placental insufficiency and inheritance versus maternal malnutrition in well-nourished populations. Acta Obstet Gynecol Scand. 2002; 81: 112–114.[CrossRef][Medline] [Order article via Infotrieve]
20. Alexander BT, Kassab SE, Miller MT, Abram SR, Reckelhoff JF, Bennett WA, Granger JP. Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide. Hypertension. 2001; 37: 1191–1195.[Abstract/Free Full Text]
21. Eder DJ, McDonald MT. A role for brain angiotensin II in experimental pregnancy-induced hypertension in laboratory rats. Clin Exper Hyper Pregnancy. 1987–1988; B6: 431–451.
22. Alexander BT, Rinewalt AN, Cockrell KL, Massey MB, Bennett WA, Granger JP. Endothelin type A receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure. Hypertension. 2001; 37 (2 pt 2): 485–489.[Abstract/Free Full Text]
23. Bauer MK, Harding JE, Bassett NS, Breier BH, Oliver MH, Gallaher BH, Evans PC, Woodall SM, Gluckman PD. Fetal growth and placental function. Mol Cell Endocrino. 1998; 140: 115–120.[CrossRef][Medline] [Order article via Infotrieve]
24. Eriksson J, Forsen T, Tuomilehto J, Osmond C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension. 2000; 36: 790–794.[Abstract/Free Full Text]
25. Leon DA, Lithell HO, Vagero D, Koupilova I, Mohsen R, Berglund L, Lithell UB, McKeigue PM. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915–1929. BMJ. 1998; 317: 241–245.[Abstract/Free Full Text]
26. Merlet-Benichou C, Gilbert T, Muffat-Joly M, Lelievre-Pegorier M, Leroy B. Intrauterine growth retardation leads to a permanent nephron deficit in the rat. Pediatr Nephro. 1994; 8: 175–180.
27. Henriksen T. Foetal nutrition, foetal growth restriction and health later in life. Acta Paediatr Suppl. 1999; 88: 4–8.[CrossRef][Medline] [Order article via Infotrieve]
28. Burns SP, Desai M, Cohen RD, Hales CN, Iles RA, Germain JP, Going TC, Bailey RA. Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation. J Clin Invest. 1997; 100: 1768–1774.[Medline] [Order article via Infotrieve]
29. Lumbers ER, Yu ZY, Gibson KJ. The selfish brain and the Barker hypothesis. Clin Exp Pharmacol Physio. 2001; 28: 942–947.[CrossRef][Medline] [Order article via Infotrieve]
30. Robillard JE, Guillery EN, Segar JL, Merrill DC, Jose PA. Influence of renal nerves on renal function during development. Pediatr Nephrol. 1993; 7: 667–671.[CrossRef][Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				V. M. Vehaskari Programming of hypertension: the nervous kidney Am J Physiol Renal Physiol, July 1, 2008; 295(1): F27 - F28. [Full Text] [PDF]

				N. B. Ojeda, D. Grigore, and B. T. Alexander Developmental Programming of Hypertension: Insight From Animal Models of Nutritional Manipulation Hypertension, July 1, 2008; 52(1): 44 - 50. [Full Text] [PDF]

				M. M. Sholook, J. S. Gilbert, M. H. Sedeek, M. Huang, R. L. Hester, and J. P. Granger Systemic hemodynamic and regional blood flow changes in response to chronic reductions in uterine perfusion pressure in pregnant rats Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2080 - H2084. [Abstract] [Full Text] [PDF]

				N. B. Ojeda, D. Grigore, E. B. Robertson, and B. T. Alexander Estrogen Protects Against Increased Blood Pressure in Postpubertal Female Growth Restricted Offspring Hypertension, October 1, 2007; 50(4): 679 - 685. [Abstract] [Full Text] [PDF]

				D. Grigore, N. B. Ojeda, E. B. Robertson, A. S. Dawson, C. A. Huffman, E. A. Bourassa, R. C. Speth, K. B. Brosnihan, and B. T. Alexander Placental insufficiency results in temporal alterations in the renin angiotensin system in male hypertensive growth restricted offspring Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2007; 293(2): R804 - R811. [Abstract] [Full Text] [PDF]

				J. P. Porter, S. H. King, and A. D. Honeycutt Prenatal high-salt diet in the Sprague-Dawley rat programs blood pressure and heart rate hyperresponsiveness to stress in adult female offspring Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R334 - R342. [Abstract] [Full Text] [PDF]

				M. Baserga, M. A. Hale, Z. M. Wang, X. Yu, C. W. Callaway, R. A. McKnight, and R. H. Lane Uteroplacental insufficiency alters nephrogenesis and downregulates cyclooxygenase-2 expression in a model of IUGR with adult-onset hypertension Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2007; 292(5): R1943 - R1955. [Abstract] [Full Text] [PDF]

				B. T. Alexander Prenatal Influences and Endothelial Dysfunction: A Link Between Reduced Placental Perfusion and Preeclampsia Hypertension, April 1, 2007; 49(4): 775 - 776. [Full Text] [PDF]

				B. N. Van Vliet and L. L. Chafe Maternal Endothelial Nitric Oxide Synthase Genotype Influences Offspring Blood Pressure and Activity in Mice Hypertension, March 1, 2007; 49(3): 556 - 562. [Abstract] [Full Text] [PDF]

				N. B. Ojeda, D. Grigore, L. L. Yanes, R. Iliescu, E. B. Robertson, H. Zhang, and B. T. Alexander Testosterone contributes to marked elevations in mean arterial pressure in adult male intrauterine growth restricted offspring Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R758 - R763. [Abstract] [Full Text] [PDF]

				M. J. De Blasio, K. L. Gatford, J. S. Robinson, and J. A. Owens Placental restriction of fetal growth reduces size at birth and alters postnatal growth, feeding activity, and adiposity in the young lamb Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R875 - R886. [Abstract] [Full Text] [PDF]

				M. Bursztyn, M.-L. Gross, T. Goltser-Dubner, N. Koleganova, T. Birman, Y. Smith, and I. Ariel Adult Hypertension in Intrauterine Growth-Restricted Offspring of Hyperinsulinemic Rats: Evidence of Subtle Renal Damage Hypertension, October 1, 2006; 48(4): 717 - 723. [Abstract] [Full Text] [PDF]

				M. Baserga, M. A. Hale, X. Ke, Z. M. Wang, X. Yu, C. W. Callaway, R. A. McKnight, and R. H. Lane Uteroplacental insufficiency increases p53 phosphorylation without triggering the p53-MDM2 functional circuit response in the IUGR rat kidney Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R412 - R418. [Abstract] [Full Text] [PDF]

				C. M. Anderson, F. Lopez, A. Zimmer, and J. N. Benoit Placental Insufficiency Leads to Developmental Hypertension and Mesenteric Artery Dysfunction in Two Generations of Sprague-Dawley Rat Offspring Biol Reprod, March 1, 2006; 74(3): 538 - 544. [Abstract] [Full Text] [PDF]

				B. T. Alexander Fetal programming of hypertension Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R1 - R10. [Abstract] [Full Text] [PDF]

				C. Infante-Rivard and C. R. Weinberg Parent-of-Origin Transmission of Thrombophilic Alleles to Intrauterine Growth-Restricted Newborns and Transmission-Ratio Distortion in Unaffected Newborns Am. J. Epidemiol., November 1, 2005; 162(9): 891 - 897. [Abstract] [Full Text] [PDF]

				V. M. Vehaskari and L. L. Woods Prenatal Programming of Hypertension: Lessons from Experimental Models J. Am. Soc. Nephrol., September 1, 2005; 16(9): 2545 - 2556. [Full Text] [PDF]

				D. J.P. Barker and S. P. Bagby Developmental Antecedents of Cardiovascular Disease: A Historical Perspective J. Am. Soc. Nephrol., September 1, 2005; 16(9): 2537 - 2544. [Abstract] [Full Text] [PDF]

				R. B. Wichi, S. B. Souza, D. E. Casarini, M. Morris, M. L. Barreto-Chaves, and M. C. Irigoyen Increased blood pressure in the offspring of diabetic mothers Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1129 - R1133. [Abstract] [Full Text] [PDF]

				S. Racasan, B. Braam, H. A. Koomans, and J. A. Joles Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon Am J Physiol Renal Physiol, April 1, 2005; 288(4): F626 - F636. [Abstract] [Full Text] [PDF]

				B. T. Alexander, A. E. Hendon, G. Ferril, and T. M. Dwyer Renal Denervation Abolishes Hypertension in Low-Birth-Weight Offspring From Pregnant Rats With Reduced Uterine Perfusion Hypertension, April 1, 2005; 45(4): 754 - 758. [Abstract] [Full Text] [PDF]

				C. M. Anderson, F. Lopez, H.-Y. Zhang, K. Pavlish, and J. N. Benoit Reduced Uteroplacental Perfusion Alters Uterine Arcuate Artery Function in the Pregnant Sprague-Dawley Rat Biol Reprod, March 1, 2005; 72(3): 762 - 766. [Abstract] [Full Text] [PDF]

				M. G. Ross, M. Desai, C. Guerra, and S. Wang Prenatal programming of hypernatremia and hypertension in neonatal lambs Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R97 - R103. [Abstract] [Full Text] [PDF]

				N. Igosheva, O. Klimova, T. Anishchenko, and V. Glover Prenatal stress alters cardiovascular responses in adult rats J. Physiol., May 15, 2004; 557(1): 273 - 285. [Abstract] [Full Text] [PDF]