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Research Article |
College of Nursing3 and Department of Pharmacology, Physiology and Therapeutics,4 University of North Dakota, Grand Forks, North Dakota, 58202
ABSTRACT
It is generally accepted that preeclampsia results from reduction in perfusion to the uteroplacental unit leading to maternal hypertension and fetal growth restriction. Placental insufficiency creates an environment of fetal undernutriton, predisposing the fetus to the development of adult disease. In this study, we characterized the development and perpetuation of hypertension in two generations of male and female offspring subjected to an environment of fetal undernutrition via reduced uteroplacental perfusion pressure. Further, we examined vascular responses of resistance arteries in these animals to determine the influence of placental insufficiency on the development and perpetuation of hypertension. Experimental dams underwent a surgical procedure to reduce uteroplacental perfusion pressure, with resulting offspring comprising the first generation (F1). One male and one female from each of the F1 experimental litters served as breeders of the second generation (F2). Weekly systolic blood pressure measurements were obtained from 4 to 24 wk in control, F1, and F2 offspring. Vascular responsiveness to the vasoconstrictors phenylephrine and potassium chloride and the vasorelaxants acetylcholine and sodium nitroprusside was determined in the three offspring groups at 6, 9, and 12 wk of age. Our findings indicate that placental insufficiency during a critical developmental window in late gestation leads to hypertension in juvenile Sprague-Dawley rat offspring and is perpetuated in a second generation of offspring in a gender-specific manner. Further, exposure to placental insufficiency during late gestation leads to developmental alterations characterized by vascular hyperresponsiveness, perpetuated to a second generation of offspring in the absence of persistent environmental stimuli, contributing to hypertension.
developmental biology
INTRODUCTION
Preeclampsia is a pregnancy-specific syndrome manifested by de novo hypertension and proteinuria in the second half of pregnancy [1]. Up to 3% of women will develop this syndrome along with the associated maternal and fetal/newborn morbidity and mortality [2]. The pathology of preeclampsia is progressive, characterized by a two-stage process [3]. Stage 1 is initiated with inadequate remodeling of the maternal spiral arterioles leading to impaired placental perfusion. Poor placental perfusion stimulates the development of local hypoxia, prompting release of factors into the maternal circulation. Stage 2 of the syndrome results from the effect of the released placental factors on the systemic maternal vasculature, characterized by enhanced vascular responsiveness. Vascular and endothelial dysfunction lead to reduced perfusion to multiple organ systems and the development of hypertension, one of the hallmarks of preeclampsia.
Placental insufficiency, both the cause and the consequence of preeclampsia, creates an environment of fetal undernutriton, altering fetal growth and predisposing the fetus to the development of adult disease [4–6]. Several investigators have suggested such intrauterine fetal stress predisposes the adult to pathologic conditions, including hypertension [7, 8]. Previous studies from our lab have demonstrated the existence of hypertension and altered vascular responsiveness in a rat model of reduced uteroplacental perfusion pressure (RUPP), an experimental model replicating the origin of pathology in preeclampsia [9, 10]. However, little is known about the mechanism of future development of hypertension in offspring exposed to the adverse fetal environment of maternal preeclampsia.
The consequences of placental insufficiency leading to fetal undernutrition are consistent with recent research findings linking impaired intrauterine nutrition, growth, and development with the development of disease later in life [11, 12]. Barker's developmental origins hypothesis proposes that cardiovascular disease results from developmental plasticity, or altered phenotype in response to adverse environmental conditions, induced by fetal undernutrition [13]. Although fetal adaptation to poor in utero nutrition may be initially adaptive, the long-term consequences resulting from the irreversible, permanent metabolic, physiologic, and structural alterations contribute to the manifestations of adult disease [11].
Evidence of cardiovascular risk perpetuated in offspring exposed to maternal preeclampsia suggests the existence of developmental alterations. The increased risk of preeclampsia in female offspring born to mothers with pregnancies complicated by preeclampsia has been well established, indicating the presence of a familial link [14, 15]. The majority of studies have focused on the risk of preeclampsia and future cardiovascular consequences in daughters of preeclamptic mothers; far fewer have explored the long-term consequences of cardiovascular disease in sons. The paternal contributions to the syndrome have stimulated consideration of preeclampsia as a couples' disease [16, 17].
In a recent study of 12-year-olds born to mothers with preeclampsia, both male and female children were found to have elevated systolic and diastolic blood pressures [18]. Further, sons born to preeclamptic mothers were twice as likely to have partners affected by preeclampsia than sons born to mothers with uncomplicated pregnancies [19]. These observations suggest a paternal link to the development of preeclampsia. Paternal polymorphisms have been shown to influence the development of preeclampsia, providing evidence to explain the paternal genetic contribution to the increased risk of preeclampsia in their partners [20]. Such genetic polymorphisms may alter susceptibility to the environmental effects of an adverse fetal environment [21], increasing the risk of developmental plasticity, or irreversible structural and functional phenotype, during a critical window of prenatal development [13].
Investigation underlying the mechanism for the development and perpetuation of hypertension in children of mothers with preeclampsia has been hampered by the absence of an authentic animal model of the human condition, because naturally-occurring preeclampsia is limited to humans. Recently, use of an animal model that mimics the origin of pathology and the typical maternal/fetal manifestations has uncovered new insights. The RUPP Sprague-Dawley rat model has been shown by our lab to produce maternal hypertension and altered fetal and placental growth [9]. Others have reported proteinuria and altered vascular responsiveness in conductance vessels in this model [22, 23]. Alteration in fetal and placental growth as a response to reduced uteroplacental perfusion has been demonstrated by our lab and others [9, 22]. Animal models of reduced uteroplacental perfusion have provided evidence of hypertension in first-generation offspring [22] as well as altered vascular responsiveness in the aorta, representative of conductance vessels [23]. These findings are consistent with the human condition preeclampsia. The influence of fetal exposure to reduced uteroplacental perfusion pressure on arterial responsiveness in resistance vessels in offspring has not been investigated. Further, perpetuation of vascular alterations to subsequent generations of offspring has not been determined.
Mechanisms underlying maternal hypertension in preeclampsia are poorly understood, although enhanced vascular responses associated with increased systemic resistance are believed to be integral to the development of hypertension [24]. The mechanisms by which cardiovascular risk is perpetuated in offspring, and variations influenced by gender, are unknown. Elucidation of the pathophysiology of the developmental origin of hypertension in offspring subjected to undernutrition and reduced perfusion in utero would provide critical insights. In this study, we characterize the development and perpetuation of hypertension in two generations of offspring subjected to an environment of placental insufficiency via reduced uteroplacental perfusion. Further, we examined vascular responses of resistance arteries in these animals to determine the influence of alterations in vascular smooth muscle function in the development and perpetuation of hypertension.
MATERIALS AND METHODS
Animals and Breeding
Approval was obtained from the University of North Dakota Animal Care Committee for all procedures involving animals. Animals were housed in an environmentally-controlled vivarium with a 12L:12D cycle. Free access to water and standard pellet diet was provided. Male and virgin female Sprague-Dawley rats were purchased from Charles River Laboratories for breeding in this study (F0). Individual female rats weighing between 230 and 300 g were paired with a single male and mated overnight for a maximum of 4 days or until the seminal plug was identified, considered Gestational Day 1. Dams were randomly selected to the control (C, n = 15) or experimental (R, n = 17) groups (see description of RUPP animal model). One male and female from each of the first-generation (F1) experimental litters were randomly selected as breeders of the second generation (F2) of offspring and bred in the manner described for F0.
Dams were individually housed after Gestational Day 1 until birth, then housed with their litters through the end of the weaning period. Offspring were identified and weighed within 12 h of birth. At 3 wk of age, offspring were separated by gender and group-housed with same-sex siblings (2–3 animals/cage). Experiments were performed on male and female offspring.
Animal Model: RUPP
The RUPP model used in this study represents an authentic model of the human syndrome preeclampsia in both origin of the condition and the resulting manifestations. On Gestational Day 14 of a normal pregnancy duration of 22–23 days, a surgical procedure to reduce uteroplacental perfusion pressure was completed in F0 experimental dams, as described previously by our lab [10, 25]. In brief, buprenorphine (0.25 mg/kg) was administered intramuscularly as preemptive analgesia, followed by an abdominal midline surgical incision made under anesthesia with a 2% isoflurane/oxygen (95%), CO2 (5%) mixture. Application of a silver clip (0.203 mm ID) to the lower abdominal aorta below the renal arteries and above the iliac bifurcation was completed to reduce uterine perfusion pressure by 
40% [26]. Application of silver clips (0.100 mm ID) to the branches of both the right and left ovarian arteries that supply the uterus was completed to prevent an adaptive increase in blood flow to the placenta. Incisions were closed in layers using appropriate suture material.
Systolic Blood Pressure
Systolic blood pressures were measured weekly in conscious, restrained rats from 4 through 24 wk of age. An automated system with a photoelectric sensor (IITC) linked to a dual channel recorder (Linseis; IITC), tail cuff, and sphygmomanometer were used to obtain indirect blood pressure measurements, which have been previously demonstrated to be closely correlated with direct arterial measurements [27]. Blood pressure measurements were repeated three times over 8 min for each animal, with the mean value recorded.
Isometric Force Measurement
Isometric force measurement was accomplished as previously described by our lab [10, 25]. In brief, rats were anesthetized and killed by thoracotomy followed by cardiac transection at 6, 9, and 12 wk of age. The mesentery was removed and immediately placed in cold physiologic saline solution (PSS) containing (in mM): 119 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 25 NaHCO3, 1.2 NaH2PO4, 0.03 EDTA, and 5.5 glucose adjusted to 7.4 pH. Mesenteric arteries (first-order) were excised and dissected free of surrounding tissues. Two arterial segments, each 2 mm in length, were mounted onto two 40-µm tungsten wires on a small vessel wire myograph for measurement of isometric force and tension in a 5-ml bath of PSS, as originally described by Mulvany and Halpern [27]. First-order arterial segments not required for isometric tension measurements were immediately frozen in liquid nitrogen and retained for use in a subsequent investigation.
Vessels were constantly exposed to 95% O2/5% CO2, slowly warmed to 37°C, and normalized [28] to achieve optimized internal circumference for development of tension. Normalized mesenteric arteries were set at 90% of internal circumference when internal pressure reached 100 mm Hg. After an equilibration period of 30 min, arteries were challenged with phenylephrine (10 µM), followed by washing with warmed PSS. Phenylephrine challenge was repeated as described for a minimum of two consecutive doses.
After an additional equilibration period of 30 min, vessels were exposed to increasing, cumulative concentrations of each of the following: phenylephrine (PE, Sigma), 10–9 to10–3.5 M; potassium chloride (KCl, Sigma), 4.7 mM, 30 mM, 60 mM, and 120 mM; acetylcholine chloride (ACh, Sigma), 10–10 to 10–6 M; and sodium nitroprusside (SNP, Sigma), 10–10 to 10–6 M. Preconstriction with phenylephrine (3 µM) was achieved before determination of relaxation responses. Vessels were thoroughly washed with PSS between doses and allowed to equilibrate for 30 min before each subsequent dose-response. Concentration-effect curves for each constrictor and relaxant were derived and used to determine vascular responsiveness.
Statistical Analyses
Concentration-effect curves generated from each vasoactive agent were displayed graphically to determine isometric tension. Drug concentrations eliciting a response of 50% (EC50) were derived and used for comparison between control, first, and second generation experimental offspring. Maximal tension (Tmax) and tension (mN/mm) at each point in the concentration-effect curve were determined. At each age point, systolic blood pressure measurements were determined. Statistical analyses in the determination of group differences were performed using a one-way ANOVA with a Tukey post hoc test for multiple comparisons. Data are expressed as mean ± SEM. All analyses were performed using GraphPad Prism Software. A value of P < 0.05 was considered significant.
RESULTS
The influence of reduced in utero perfusion on postnatal vascular function was determined in animals directly exposed to the fetal environment of undernutrition (F1) and in animals indirectly exposed, the offspring of the directly exposed animals (F2). Isometric tension in response to 
1-adrenergic receptor-mediated vasoconstriction with incrementally increasing concentrations of PE was measured in control, F1, and F2 offspring at 6, 9, and 12 wk of age. Figure 1 details differences between groups in vascular responsiveness at each point of the concentration-effect curve in male and female offspring. In male offspring, reduced in utero perfusion led to a significant increase in Tmax at 6 (P < 0.001), 9 (P < 0.05), and 12 (P < 0.05) wk of age. Tmax was significantly greater in F2 as compared to age-matched controls at each age interval (6 wk, 8.91 ± 0.57 vs. 4.88 ± 0.53 mN/mm, P < 0.001; 9 wk, 9.93 ± 0.45 vs. 6.47 ± 0.60 mN/mm, P < 0.05; 12 wk, 10.05 ± 1.03 vs. 7.08 ± 0.65 mN/mm, P < 0.05). At 6 wk of age, Tmax was increased in F2 compared to F1 (6.4 ± 0.38 mN/mm, P < 0.05). In F1 offspring, Tmax was increased over control at 9 wk of age (9.09 ± 0.84 mN/mm, P < 0.05). No other group differences in Tmax were determined. EC50 was not significantly different between groups.
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Among female offspring, reduced in utero perfusion effected a significant increase in Tmax at 9 and 12 wk (P < 0.01) of age. At 9 wk, Tmax was significantly greater in F2 (8.73 ± 0.41, mN/mm, P < 0.01) as compared to age-matched controls (5.84 ± 0.42 mN/mm). At 12 wk of age, Tmax was increased in F1 (9.05 ± 0.5 mN/mm, P < 0.01) and F2 (8.79 ± 0.98 mN/mm, P < 0.05) experimental groups as compared to control (6.1 ± 0.23 mN/mm), but not significantly different between experimental groups. EC50 was significantly different between F1 and F2 females at 12 wk of age (F1, log –5.69 + 0.49; F2, log –6.04 + 0.05; P < 0.05), though no significant difference was noted between experimental groups and control.
Mesenteric arteries were challenged with increasing concentrations of KCl to determine voltage-mediated vasoconstrictor responsiveness. Maximal mean tension at increasing concentrations of KCl is detailed in Figure 2. Among male offspring, Tmax was increased in response to in utero reduction in perfusion at all age points in F2 as compared to control offspring (6-wk F2 4.4 ± 0.18 vs. control 2.41 ± 0.31 mN/mm, P < 0.001; 9-wk F2 5.25 ± 0.51 vs. control 3.07 ± 0.27 mN/mm, P < 0.01; 12-wk F2 5.8 ± 0.57 vs. control 3.89 ± 0.46 mN/mm, P < 0.05). There were no other significant differences in Tmax between groups. No significant differences in EC50 were determined. Within female offspring groups, Tmax was increased in response to in utero reduction in perfusion (P < 0.05) at 6 (control, 1.97 ± 0.25 mN/mm; F1, 3.16 ± 0.46 mN/mm; F2, 3.41 ± 0.27 mN/mm), 9 (control, 2.74 ± 0.16 mN/mm; F1, 3.96 ± 0.45 mN/mm; F2, 4.22 ± 0.28 mN/mm), and 12 (control, 3.21 ± 0.12 mN/mm; F1, 4.9 ± 0.27 mN/mm; F2, 4.29 ± 0.65 mN/mm) wk of age. No significant differences in EC50 were identified.
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Endothelium-dependent relaxation was examined by analysis of vascular responses to acetylcholine. Vessels were preconstricted, ensuring that all vessels achieved 0% relaxation before application of increasing concentrations of the endothelium-dependent relaxation agent ACh. Changes in tension at each concentration increment were determined (Fig. 3). There were no significant differences in EC50 at any age point among male offspring. EC50 was significantly different between female offspring groups at 9 wk of age (P < 0.05), with enhanced relaxation responses evident in the F1 experimental group as compared to control. No further differences in EC50 were found at 6 or 12 wk of age among females. Relaxation responses were increased in the F1 female experimental group at 9 wk (10–9, P < 0.05; 10–8, P < 0.01) and at 12 wk of age (10–9, P < 0.01) as compared to age-matched controls (Fig. 3). No significant effect was seen between F2 female offspring and control. Reduced in utero perfusion induced an enhanced endothelium-dependent relaxation effect in F1 female experimental offspring compared to control at 9 wk (P < 0.05).
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Endothelium-independent relaxation responses were determined in mesenteric arteries exposed to increasing concentrations of sodium nitroprusside (SNP). Preconstricted mesenteric arteries were challenged with increasing concentrations of the endothelium-independent relaxation agent SNP (Fig. 4). Enhanced relaxation was evident in the mesenteric arteries from F2 male offspring (13 ± 6.33%, P < 0.05), compared to control (4.4 ± 1.29%) at the lowest SNP concentration (10–10). This finding was limited to animals at 9 wk of age. No significant differences in EC50 were determined within the male offspring groups. Consistent with relaxation responses to ACh, the EC50 in mesenteric arteries from female animals in the 9-wk F1 experimental group indicated enhanced responsiveness to SNP as compared to control (P < 0.01) and F2 (P < 0.05) experimental animals at the same age. No further differences in EC50 were found in other age groups among female offspring. Mesenteric arteries from F1 female experimental animals had increased dose-dependent relaxation responses to SNP as compared to control at 9 (10–10, P < 0.05; 10–8, P < 0.01) and 12 wk of age (10–10, P < 0.01; 10–9, P < 0.01).
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Systolic blood pressure measurements were completed to determine the functional consequences of fetal exposure to placental insufficiency. Systolic blood pressure was determined on all experimental F1, F2, and control offspring from 4 to 24 wk of age, summarized by 3-wk increments in Figure 5. The size of each group was reduced after 6-, 9-, and 12-wk age points because of the loss of animals required for associated vascular isometric tension studies. At all age points from 4 to 12 wk, there were significant group differences in systolic blood pressure induced by reduction in perfusion (P < 0.001) among male offspring. Marked increases in systolic blood pressure were evident in F1 compared to control male offspring at all age points (P < 0.001). A similar trend was apparent in F2 male offspring as compared to control at 5 wk (P < 0.01), persisting through 12 wk of age (6–12 wk, P < 0.001). A subgroup of control, F1, and F2 male offspring (n = 10, each group) was followed for determination of systolic blood pressure measurement in advancing age from 13 through 24 wk of age. Significant systolic blood pressure increases persisted in F1 and F2 offspring throughout this time period (P < 0.001) as compared to control . There were no significant differences in blood pressure of F1 offspring compared to F2 measurements between 13 and 24 wk of age. From 13 to 24 wk, blood pressure averaged 114.3 ± 0.27 mm Hg (range, 112.8–115.6 mm Hg) in control males, 137.7 ± 0.48 mm Hg (range, 134.7–139.8 mm Hg) in F1 males, and 136.1 + 0.57 mm Hg (range, 132.5–138.8 mm Hg) in F2 males.
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Female offspring demonstrated significant group differences in systolic blood pressure induced by placental insufficiency within all age groups (P < 0.001). Marked increases in systolic blood pressure were evident in F1 compared to control female offspring at all age points excluding 4 wk (P < 0.001). In contrast, F2 female offspring had significantly lower systolic blood pressure at 4 (100.3 ± 5.87 vs. 114.9 ± 0.70 mm Hg, P < 0.001, F2 vs. control respectively) and 5 wk (105.5 ± 5.71 vs. 116.8 ± 0.94 mm Hg, P < 0.05, F2 vs. control, respectively) than their age-matched female control counterparts. No further significant differences in systolic blood pressure between F2 and control females were found until 9 wk of age, when systolic blood pressure of F2 female offspring was significantly increased over control (127.5 ± 1.18, n = 38 vs. 115.2 ± 0.44, n = 58, P < 0.001, F2 vs. control respectively). This pattern persisted through 12 wk of age (130.5 ± 0.79, n = 27, vs. 113.3 ± 0.42, n = 43, P < 0.001, F2 vs. control respectively). Blood pressure in both F1 and F2 females remained significantly increased over control through 24 wk of age (P < 0.001). Between 13 and 24 wk of age, blood pressure averaged 114.1 ± 0.41 mm Hg (range, 111.5–116.4 mm Hg) in control females, 137.6 ± 0.64 mm Hg (range, 133.4–141 mm Hg) in F1 females, and 135 ± 0.36 mm Hg (range, 132.6–136.5 mm Hg) in F2 females. Systolic blood pressure in F1 offspring was significantly increased over F2 (P < 0.001), with the exception of 10 wk and 16–24 wk of age, when no statistically significant difference was found.
DISCUSSION
Maternal undernutrition has been linked to the developmental origin of hypertension [29]. In this study, we investigated the development and perpetuation of enhanced vascular responsiveness and impaired vascular relaxation in two consecutive generations of rats. The first-generation offspring were born to mothers with surgical reduction in perfusion to the fetal/placental unit. The second-generation offspring were born to first-generation dams and sires, without additional intervention during gestation. To address the implications for future development of disease in response to fetal undernutrition via placental insufficiency, measurements of systolic blood pressure were completed to identify the development and perpetuation of hypertension. We have previously shown that reduced uteroplacental perfusion leads to maternal hypertension and indices of fetal growth restriction [9]. Further, evidence of hypertension in first-generation offspring born to dams exposed to RUPP has also been reported [22]. The current study was designed to extend these observations and to determine whether vascular responses in resistance arteries were altered in offspring. Our findings indicate that blood pressure was elevated and vasoconstrictor responsiveness was enhanced in both first- and second-generation experimental offspring. To our knowledge, these are the first findings that have linked vascular alterations with the perpetuation of hypertension in second-generation offspring.
Previous studies have demonstrated altered vascular responsiveness and hypertension in adult offspring subjected to maternal dietary undernutrition during fetal development [30]. Dietary variations may contribute to inconsistency in findings related to developmental origins of disease. The use of an animal model producing fetal undernutrition through reduced uteroplacental perfusion, consistent with the human condition preeclampsia, provides an authentic, consistent environment from which to study development and perpetuation of disease originating during fetal development. The RUPP Sprague-Dawley animal model used in this study promotes similar maternal and fetal manifestations of the human condition preeclampsia, including maternal hypertension and fetal growth restriction. Therefore, the use of the RUPP model to further elucidate the mechanism contributing to the development and perpetuation of hypertension in offspring represents a consistent, reliable model to evaluate the development of hypertension resulting from undernutrition caused by placental insufficiency.
The trend toward enhanced responsiveness to -1 adrenergic- and voltage-mediated constrictor stimuli was evident in both genders and generations of experimental offspring. It is interesting to note that these trends were perpetuated in the second generation of offspring, suggesting a genetic link. The findings of this study indicated that placental insufficiency triggered hyperresponsiveness of mesenteric arteries in first-generation male and female offspring. Further, these effects were propagated to a second generation, in the absence of surgical reduction in placental perfusion. Enhanced responsiveness occurred in the absence of endothelium-dependent and endothelium-independent impaired relaxation responses, suggestive of enhanced vascular smooth muscle vasoconstrictor signaling.
The development of hypertension in response to placental insufficiency was similar in first-generation male and female experimental offspring. Increased systolic blood pressure was evident in first-generation female experimental offspring as early as 5 wk of age, and 4 wk of age in first-generation male experimental offpsring, persisting through 24 wk in both genders. These findings indicate that placental insufficiency during a critical developmental window in late gestation leads to juvenile-onset hypertension, persisting into adulthood in Sprague-Dawley rat offspring.
Significant gender differences were evident in the second-generation offspring. Second-generation male offspring exhibited a significantly increased systolic blood pressure by 5 wk of age compared to control. In contrast, female second-generation experimental offspring had significantly lower blood pressures, compared to both first-generation experimental and control females in the early juvenile period. Systolic blood pressure increased significantly over control by 9 wk of age, just before reproductive maturity. The underlying mechanisms contributing to these differences are not known, but may provide insight into the mechanisms underlying the developmental origins of hypertension. Our study provides the first evidence of the perpetuation of alterations in vascular function associated with the fetal origins of hypertension to a second generation of offspring. Furthermore, our data suggest that hyperresponsiveness to vasocontrictors, rather than impaired relaxation response, may provide an explanation for the developmental origins of hypertension.
Conclusions from this study demonstrate the intergenerational effects of fetal undernutrition in the absence of persistent environmental stimuli, lending further support to the developmental origins of hypertension. The experimental design of this animal study reduces confounding variables thought to impact epidemiological studies indicating similar intergenerational trends in humans. Characterization of alterations in vascular responsiveness induced by fetal undernutrition provides important evidence in exposing the mechanisms leading to the development and perpetuation of hypertension in offspring. Investigation into the specific signaling alterations in vascular smooth muscle will provide mechanistic insights into the developmental origins of hypertension. Our data suggest that an adverse fetal environment triggers persistent alterations in cardiovascular function and has far-reaching implications for subsequent generations.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the statistical review provided by LuAnn Johnson, Grand Forks Human Nutrition Research Center.
FOOTNOTES
2 Correspondence: Cindy M. Anderson, Box 9025, College of Nursing, University of North Dakota, Grand Forks, ND 58202-9025. FAX: 701 777 4096; cindyanderson{at}mail.und.nodak.edu 
1 Supported by the University of North Dakota Faculty Seed Money Council; Sigma Theta Tau International, Eta Upsilon Chapter; University of North Dakota College of Nursing (C.M.A.); and National Institute of Digestive, Diabetes and Kidney Disease (J.N.B.) DK51430.
Received: 20 July 2005.
First decision: 8 August 2005.
Accepted: 23 November 2005.
REFERENCES
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  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]
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 G. Wu, F. W. Bazer, J. M. Wallace, and T. E. Spencer BOARD-INVITED REVIEW: Intrauterine growth retardation: Implications for the animal sciences J Anim Sci, September 1, 2006; 84(9): 2316 - 2337. [Abstract] [Full Text] [PDF]
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control vs. F2; #F1 vs. F2). Animals in each group totaled five in control groups at all ages and in 6-wk experimental F1 and F2 groups. Nine- and twelve-week F1 and F2 experimental groups totaled four animals each. Data are expressed as mean ± SEM
