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Pregnancy |
Department of Animal Science2
Department of Zoology,3 University of Wyoming, Laramie, Wyoming 82071-3684
Department of Obstetrics and Gynecology,4 New York University School of Medicine, New York, New York 10016
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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conceptus, placenta, placental transport, pregnancy, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Growth and carcass characteristics of ruminants vary considerably even when genetics and nutritional management are constant. These differences in animal performance and composition have been attributed to variations in both endogenous and exogenous hormonal status [4] and to the general health and immune status [3] of the animal. Epidemiological studies in humans have revealed that undernutrition during the first half of pregnancy alters fetal growth and development, predisposing offspring to cardiovascular, metabolic, and endocrine diseases in adult life [5–8]. In sheep, as well as humans, the first half of gestation is critical for proper fetal organogenesis and placental growth and vascularization [9–11]. Further, the structure of fetal blood vessels (stem arteries and veins, intermediate arterioles and venules, and terminal capillaries) in sheep and humans are comparable [12], suggesting similarities in fetal placental vascular development. Vascular endothelial growth factor (VEGF), a potent angiogenic [13] and permeability [14] factor, is present in the cotyledon of the ovine placentome [15] and is regulated by hypoxia [16] and estrogen [17]. It is probable that undernutrition in the dam may impact placental vascularity and the transport of nutrients and oxygen to the growing fetus. Although several investigations [18–20] have looked at a moderate and decreasing nutrient restriction during gestation in the ewe, none resulted in significant losses in maternal body weight or fetal weight during the restriction period. Further, none of these studies evaluated the impact of undernutrition on placentomal (cotyledonary/caruncular) vascularity.
We hypothesized that a constant reduction in nutrient intake to 50% NRC [21] requirements from Days 28 through 78 of gestation would decrease maternal body weight and reduce the growth and development of the ovine fetus. More specifically, the objectives of this study were to analyze the impact of a constant nutrient restriction on maternal and fetal body weights and selected organ weights, as well as placentomal numbers, weights, morphologies, and vascularities. In addition, the impact of nutrient restriction on levels of glucose, tri-iodothyronine (T3) and thyroxine (T4), estradiol-17ß (E2-17B), and progesterone (P4) in maternal and fetal blood and vascular endothelial growth factor (VEGF) in fetal blood were evaluated.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All animal procedures were approved by the University of Wyoming Animal Care and Use Committee. On Day 20 of pregnancy, 13 multiparous ewes of mixed breeding were weighed so that individual diets could be calculated on a metabolic body weight basis (weight0.75). The diet consisted of a pelleted beet pulp (79.7% total digestible nutrients [TDN], 93.5% dry matter [DM], and 10.0% crude protein). Rations were delivered on a DM basis to meet the total TDN required for maintenance for an early pregnant ewe (NRC requirements [21]). A mineral-vitamin mixture (51.43% sodium triphosphate, 47.62% potassium chloride, 0.39% zinc oxide, 0.06% cobalt acetate, and 0.50% ADE vitamin premix [8 000 000 IU vitamin A, 800 000 IU vitamin D3, and 400 000 IU vitamin E per pound; amount of vitamin premix was formulated to meet the vitamin A requirements]) was included with the beet pulp pellets to meet requirements. On Day 21 of gestation, all ewes were placed in individual pens and fed control rations. On Day 28, ewes were randomly assigned to a control-fed group (n = 7; 100% NRC requirements [21], which included 100% mineral-vitamin mixture) and a nutrient-restricted group (n = 6; fed 50% NRC requirements [21], which included 50% mineral-vitamin mixture). Beginning on Day 28 of gestation and continuing at 7-day intervals, ewes were weighed and rations adjusted for weight gain (i.e., increased the amount of feed) or loss (i.e., decreased the amount of feed). On Day 45 of gestation, the numbers of fetuses carried by each ewe was determined by ultrasonography (Ausonics Microimager 1000 sector scanning instrument; Ausonics Pty Ltd, Sydney, Australia).
Just prior to ewes being killed on Day 78 of gestation, each ewe was weighed and a sample of blood collected via jugular venipuncture into a heparinized vacutainer tube (sodium heparin, 143 USP units, Becton Dickinson, Franklin Lakes, NJ) for T3, T4, P4, and E2-17B determination and into a separate tube (heparin plus sodium fluoride; 2.5 mg/ml; Sigma, St. Louis, MO) for glucose determination. Ewes were then given an overdose of sodium pentabarbitol (Abbott Laboratories, Abbott Park, IL) and exanguinated, and the gravid uterus was quickly removed and weighed.
The tip of the gravid uterine horn was opened to expose the fetus, and the umbilical cord was located. Umbilical cord blood was collected into a heparinized vacutainer tube for T3, T4, P4, E2-17B, and VEGF and a tube containing heparin plus sodium fluoride for glucose determination. Fetal weights, crown-rump lengths, abdominal circumferences and sex, and the weights of the liver, pancreas, lung, kidney, adrenal, and the left ventricle, right ventricle, and septum of the heart were recorded. Maternal and fetal blood were collected into cooled tubes and placed on ice and centrifuged (4°C, 3000 g, 10 min). Maternal and fetal plasma were stored at -80°C until analyzed.
After removal of the fetus, a type A placentome [22] located 
10 cm from the umbilicus was selected, dissected from the surrounding tissues and weighed. A cross section of the placentome was placed in a tissue cassette (Tissue Tek, Miles Labs, Elkhart, IN) and fixed with paraformaldehyde and paraffin embedded. Twelve 5-µm sections evenly spaced over a 450-µm area of each placentome were evaluated for vascular density via image analysis [23] (Optimus Image Analysis Software, Bothell, WA). Briefly, maternal and fetal blood vessels were counted and traced within four fields per section at points where the caruncular and adjacent cotyledonary tissue of the placentome could be visualized (Fig. 1). The blood vessel area per unit tissue area (i.e., caruncular blood vessel area/caruncular area; cotyledonary blood vessel area/cotyledonary area), number of blood vessels per unit tissue area (i.e., caruncular blood vessel number/caruncular area; cotyledonary blood vessel number/cotyledonary area), and blood vessel diameters were calculated. All remaining placentomes were removed and weighed, and their diameter and morphologic type (based on the classification scheme of Vatnick et al. [22]) were recorded. By using the diameter measurements previously recorded, the surface area of each placentome was calculated by using the formula 
r2 (r = radius). Thereafter, the cotyledonary tissue was peeled away from the caruncular tissue of each placentome and the components from all placentomes pooled so that total caruncular and total cotyledonary weights could be determined.
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Maternal organs including the pituitary gland, adrenal gland, liver, and left ventricle, right ventricle, and septum of the heart were removed from the body cavity and weighed. The reticulo-rumen, omasum, abomasum, and entire gastrointestinal tract were emptied of their contents and weighed, and maternal empty body weights were recorded.
Assays
Glucose was analyzed using a colorimetric assay according to manufacturer's specifications (Sigma, Glucose catalog no. 115-A). Within-assay variability for glucose was determined by assaying a high and low pool of systemic plasma from pregnant ewes. The intraassay and interassay (n = 7) coefficients of variation (CV) were 4.5% and 13.5% versus 13.1% and 19.4% versus for the high and low pools, respectively.
Estradiol-17ß was quantified in 1-ml maternal and fetal plasma samples. Extraction, chromatography, and radioimmunoassay (RIA) procedures were identical to procedures previously validated in this laboratory for ovine plasma and using the same fully characterized antibody [24]. All samples were analyzed in the same assay; intraassay CV was <10%.
Progesterone was measured via a specific RIA previously validated in our laboratory for pregnant ewe plasma [25] utilizing the same fully characterized antibody, GDN-337 [26]. All samples for P4 determination were run in a single assay (intraassay CV = 7.1%). Tri-iodothyronine and T4 were determined by RIA according to manufacturer's specifications (Coat-a-Count Total T3 and T4, DPC, Los Angeles, CA). All blood plasma samples were assayed in a single assay. The intraassay CV was 8.8% and 7.7% for T3 and T4, respectively.
An RIA for VEGF was developed for sheep plasma samples according to the protocol of Anthony et al. [27] with modifications. Human, recombinant VEGF165 (cold hormone; G143AB; Genentech, Inc., Los Angeles, CA), primary antibody (polyclonal rabbit antiserum to VEGF165; #27906–17, Genentech, Inc., Los Angeles, CA) and human, recombinant [125I]-VEGF165 (tracer; NEX328, NEN Life Science Products, Inc., Boston, MA) were used in all assays. The 165-isoform of VEGF exists as a soluble form [28] and is the most abundant isoform expressed in ovine placental tissues [15]. Sensitivity averaged 25 pg/ml, defined as the VEGF standard yielding 95% of the counts in the buffer control tube. Within-assay variability for VEGF was determined by assaying a pool of systemic plasma from a pregnant ewe to which known quantities of VEGF had been added (0.0, 0.5, and 5.0 ng/ml plasma). The resulting concentrations (±SEM), after subtraction of the plasma blank (1.46 ± 0.11 ng/ml), averaged 0.62 ± 0.04 (n = 4) and 5.42 ± 0.16 (n = 4) ng/ml, respectively. Coefficients of variation averaged 10.7%, 8.2%, and 5.8% for the plasma blank and 0.5- and 5.0-ng/ml VEGF additions, respectively. Parallelism was obtained between a doubly diluted pregnant plasma pool and the standard curve. No cross-reactivity was found with basic fibroblast growth factor or 
2-macroglobulin (Sigma) at concentrations as high as 100 mg/L.
Statistics
Data were analyzed by a factorial analysis of variance using the PROC GLM and PROC CORR procedures of SAS (SAS Institute Inc., Cary, NC). There was no effect of sex on any of the measurements taken; therefore, data were pooled across sex. Class statements included diet and number of fetuses. Model statements included the effects of diet and fetal number on fetal weight, fetal crown-rump length, fetal organ weights, fetal organ weights divided by the weight of the fetus, placentomal number, placentomal surface area, placentomal weight, total caruncular weight, total cotyledonary weight, diameters of blood vessels in caruncular and cotyledonary tissues, blood vessel diameters, blood vessel area per unit area caruncular and cotyledonary tissue and numbers of blood vessels per unit area caruncular and cotyledonary tissues, progesterone, glucose, T3, T4, and VEGF. Means separation was performed using LSMEANS. Correlations between these variables were also performed. Means ± SEM were considered different when P < 0.05 unless otherwise stated.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The number of fetuses gestated by each ewe on Day 45, as determined by ultrasonography, was identical to the number present on Day 78, demonstrating no fetal loss during the subsequent course of nutrient restriction. Additionally, the lack of fetal loss was confirmed by counting the number of corpora lutea on the ovaries of each ewe at tissue collection. The control-fed group had three singleton and four twin pregnancies, while the nutrient-restricted group had four singleton and two twin pregnancies.
Concentrations of E2-17B and P4 in systemic circulation of nutrient-restricted and control-fed ewes were similar immediately prior to killing (Table 2). In contrast, nutrient-restricted ewes had decreased (P < 0.05) plasma glucose concentrations and an increased (P < 0.05) plasma T4/T3 ratio when compared to control-fed ewes (Table 2). Similarly, glucose concentrations in fetal blood were also decreased (P < 0.05) in fetuses from nutrient-restricted versus control-fed ewes (Table 3). While T3 concentrations were undetectable in fetal blood, T4 concentrations were decreased (P < 0.05) in twin fetuses from nutrient-restricted ewes when compared with singleton and twin fetuses from control-fed ewes and singleton fetuses from nutrient-restricted ewes (Table 3). Vascular endothelial growth factor and E2-17B concentrations in fetal blood were similar across singleton and twin pregnancies of both treatment groups, averaging 0.63 ng/ml and 71.75 pg/ml, respectively.
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Fetuses from control-fed ewes were markedly (P < 0.01) heavier and larger (> crown rump length, CRL) than fetuses from nutrient-restricted ewes (Table 4). However, there was no difference in abdominal circumference of the fetuses from control-fed or nutrient-restricted ewes. There was no difference (P > 0.10) in weight or CRL between singleton and twin fetuses gestated by control-fed ewes (325.97 ± 34.99 g and 23.00 ± 1.26 cm vs. 326.51 ± 25.57 g and 23.75 ± 0.54 cm, respectively). In contrast, singleton fetuses were heavier (P < 0.05) and tended to be larger (P < 0.10) than twin fetuses in the nutrient-restricted group (240.75 ± 2.90 g and 22.38 ± 1.03 cm vs. 202.60 ± 6.37g and 20.75 ± 0.48 cm, respectively).
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Fetal liver, lungs, and kidneys from nutrient-restricted ewes were reduced (P < 0.05) in weight when compared to those of control-fed ewes (Table 4). When corrected for fetal weight, however, all organ weights evaluated were similar between fetuses gestated by nutrient-restricted and control-fed ewes with the exception of the liver and the right and left ventricles of the heart, which were greater (P < 0.05) per unit fetal weight in the nutrient-restricted ewes.
Total numbers of placentomes in gravid uteri of control-fed ewes were similar to numbers found in nutrient restricted ewes (88 ± 3 vs. 80 ± 4, respectively). Further, numbers of placentomes associated with singleton fetuses (84 ± 5) were double (P < 0.01) the numbers associated with a twin fetus (42 ± 2) across both treatment groups. While similar numbers of placentomes were associated with twin fetuses of control-fed and nutrient-restricted ewes, numbers of placentomes were greater (P < 0.05) for singleton fetuses from control-fed ewes when compared to the number in nutrient-restricted singleton fetuses from nutrient-restricted ewes (92 ± 4 vs. 78 ± 6, respectively). There was no difference in the range or distribution of placentomal weight between conceptuses of control-fed or nutrient-restricted ewes (Fig. 3). Similar to placentomal weight, there was no difference in the range or distribution of placentomal surface area between conceptuses of the control-fed and nutrient-restricted groups (Fig. 4). Further, there was no effect of twin versus singleton pregnancies on the range or distribution of placentomal weight or surface area. There were no effects of treatment or fetal number on the placentomal types observed, with virtually all placentomes being classified as type A (i.e., caruncular tissue completely surrounding the cotyledonary tissue) for all animals. In contrast, a significant effect (P < 0.05) of twin versus single pregnancies was observed in the surface area of individual placentomes (Fig. 5). Individual placentomes associated with a singleton conceptus had reduced (P < 0.05) surface areas than those associated with a twin conceptus (i.e., a greater percentage of smaller placentomes [<10 cm2] were associated with the singleton fetuses vs. twin fetuses).
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In agreement with the data presented here, there were no differences (P > 0.05) in total placentome weight and surface area or total caruncular and cotyledonary weights between conceptuses from control-fed and nutrient-restricted ewes (Table 5). As would be expected from the greater numbers of placentomes present, singleton fetuses, regardless of treatment, had markedly (P < 0.01) heavier total placentome weight as well as caruncular and cotyledonary weights than twin fetuses. Table 5 depicts the ratios of fetal weight to cotyledonary, caruncular, and total placentomal weights. Conceptuses from nutrient-restricted ewes exhibited reduced ratios of fetal weight/cotyledonary weight, fetal weight/caruncular weight, and fetal weight/total placentome weight when compared to conceptuses from control-fed ewes.
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Although nutrient restriction did not affect the size or morphologic type of placentomes on Day 78, placentomal vascularity was impacted. There was a 3-fold increase (P < 0.05) in the number of caruncular blood vessels per unit area tissue of twin conceptuses from nutrient-restricted ewes when compared to singleton and twin conceptuses recovered from control-fed ewes or singleton conceptuses recovered from nutrient-restricted ewes (Table 6). The number of cotyledonary blood vessels per unit area tissue did not differ between groups. There was no difference in the area of blood vessels per unit tissue area in either the caruncular or the cotyledonary tissue in any of the fetal groups. Further, while caruncular blood vessel diameter was larger (P < 0.05) than cotyledonary blood vessel diameter, there was no treatment effect in blood vessel diameter of either the caruncular blood vessels (266.40 ± 31.50 µm) or the cotyledonary blood vessels (70.37 ± 5.40 µm).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Concentrations of T4 were reduced in the blood of twin fetuses gestated by nutrient-restricted ewes when compared to fetuses from control-fed ewes or singleton fetuses from nutrient-restricted ewes, suggesting a further nutrient associated reduction in fetal metabolic rate in these twins. Most of the T4 in fetal mammals is deiodinated to the inactive metabolite, rT3, via an iodothyronine 5-monodeiodinase in fetal tissue [32, 33]. In the fetal sheep, the ability to convert T4 to active T3 does not occur until the third trimester of gestation [33], which explains our inability to detect T3 in fetal blood on Day 78 of gestation.
While Clarke et al. [18] and Heasman et al. [19] progressively increased the amount of feed given to each ewe with advancing gestation to comply with the Agricultural and Food Research Council [34] guidelines, we adjusted feed intake up (control fed) or down (nutrient restricted) based only on gains or losses in ewe body weight. Orskov and Ryle [35] reported that the ruminant becomes more efficient in utilizing nutrients when energy requirements are not met (e.g., during fasting). Thus, in contrast to Clarke et al. [18], who reported no differences in ewe body weight regardless of dietary regimen, nutrient-restricted ewes in our study lost a significant amount of weight, while control-fed ewes gained an equivalent amount of weight during the treatment period in accordance with the advancement of normal pregnancy in sheep. As the average control-fed ewe in this study gained 7.5% of her initial body weight by Day 78 of gestation, one could consider that our nutrient-restricted ewes actually lost 15% of predicted weight (7.5% predicted weight gain plus 7.4% actual weight loss). The reduced body weight in the nutrient-restricted ewes is not due strictly to gastrointestinal tract fill, as the empty body weight at the end of the study was also reduced, indicating a loss of fat and/or muscle in the nutrient-restricted ewes compared to the control-fed ewes.
Fetuses from nutrient-restricted ewes were markedly lighter than those from control-fed ewes but exhibited individual organs that were not uniformly reduced in weight. Increased liver weight per unit fetal weight in fetuses from nutrient-restricted ewes compared to control-fed ewes may be explained by an increase in liver metabolic activity imperative for development. It has been reported that glucose requirements of the growing ovine fetus are met largely via placental uptake of maternal glucose [36] and that maternal and fetal blood glucose concentrations are highly correlated [37]. Lemons et al. [38] reported that when ewes are fasted at 120 days of gestation, the gluconeogenic enzymes (e.g., glucose-6-phosphatase, glutamate pyruvate transaminase, phosphoenolpyruvate carboxykinase) are increased in fetal liver. As ruminants depend primarily on gluconeogenesis rather than intestinal glucose absorption to meet their glucose requirement [39], it was suggested that even the fetal liver has the potential to perform this metabolic function in utero when glucose requirements are not met. Further investigation into the gluconeogenic properties of the fetal liver is warranted.
Of interest is the observation that the right and left ventricles of the heart were larger per unit body weight in fetuses from nutrient-restricted than control-fed ewes, thereby demonstrating a bilateral ventricular hypertrophy. This condition is suggestive of increased ventricular afterload (i.e., the force that a ventricle must overcome while it contracts during ejection), seen in human fetuses using high-resolution echocardiography [40]. The components that contribute to increased ventricular afterload are aortic or pulmonary artery impedance, peripheral vascular resistance, and mass and viscosity of blood. The observation of bilateral ventricular hypertrophy is exciting, as Samson et al. [41] reported that no animal model has been developed that reproduces the observations in the human fetus associated with increased left-ventricular afterload. Previous models using the fetal lamb have invariably resulted in left-ventricular hypertrophy without right-heart enlargement [42, 43]. Thus, this model of early fetal nutrient deprivation in the sheep may also serve as a relevant model to study the etiology and consequences of human fetal ventricular hypertrophy.
We hypothesize that the bilateral increase in fetal ventricular weights from the nutrient-restricted ewes may be due to an increase in placental vascular resistance. Rigano et al. [44] demonstrated that umbilical vein blood flow is reduced in intrauterine growth-restricted (IUGR) fetuses as a result of reduced umbilical vein blood flow velocity. Further, reduced umbilical blood flow, increased umbilical arterial pulsatility index, and increased placental vascular resistance have been reported for both human and sheep IUGR pregnancies [45–48]. The reduced ratios of fetal weight to cotyledonary, caruncular, and total placentome weight on Day 78 of gestation indicate that there is a reduced placentomal function of the conceptuses from nutrient-restricted ewes, possibly due to a decrease in the amount of nutrients delivered to the developing fetus. Although no diet-associated differences in placental weight or placentome numbers, sizes, or morphologies were observed in the present study, we did observe that twin conceptuses had reduced numbers of placentomes, with a greater percentage of those placentomes having a larger surface area than those associated with singleton fetuses. Further, marked increases were observed in the caruncular vascular density of placentomes from twin conceptuses gestated by nutrient-restricted ewes. The number of caruncular, but not cotyledonary, blood vessels per unit area in nutrient-restricted ewes carrying twins was 3-fold greater than that in control-fed ewes carrying singles or twins or nutrient-restricted ewes carrying twins. Morris et al. [49] demonstrated a 25% reduction in uterine blood flow and a 20% decrease in placental blood flow of ewes fasted for 5 days prior to evaluation on 100 days of gestation. The decrease in nutrient availability, as well as the stress of carrying twins, may have increased caruncular vascularity in order to compensate for decreased nutrient delivery. Despite the increase in caruncular vascularity, there was no corresponding increase in the numbers of cotyledonary blood vessels in placentomes of restricted twins, potentially negating the impact of increases in caruncular vascular numbers on Day 78 of gestation. However, since cotyledonary vascularity increases markedly after Day 80 in the ewe [9], overall vascularity of the placentome may be greater in the nutrient-restricted ewes compared to control-fed ewes by term.
Vascular endothelial growth factor is a potent angiogenic factor at the fetal:maternal interface in both cotyledonary and caruncular tissue [50], and its expression is known to be increased by estrogen [16] and hypoxia [17]. In the pig conceptus, both VEGF mRNA [51] and protein expression (S.P. Ford, unpublished observations) are highly correlated with placental vascularity late in gestation (Days 70–110 of gestation). Both fetal demand for oxygen and placental secretion of estrogen increase dramatically in late gestation in both the pig and the sheep. In this regard, we have demonstrated no treatment differences in P4 or E2-17B concentrations in either fetal or maternal blood, suggesting that there is no interruption in normal steroidogenesis occurring between our control-fed and nutrient-restricted ewes. Further, we observed no differences in VEGF concentrations in fetal cord blood from nutrient-restricted and control-fed ewes. This observation is not surprising, as Carnegie and Robertson [52] show a dramatic increase in fetal plasma estrogen only after Day 80 of gestation in the ewe. This dramatic increase in placental estrogen production after Day 80 of gestation is temporally associated with the marked increases in cotyledonary VEGF mRNA expression [15], cotyledonary vascular density [9], and uterine blood flow [53]. It is possible that the increased caruncular vascularity of twin conceptuses from nutrient-restricted ewes in this study might facilitate an augmented nutrient delivery to these undersized fetuses during a realimentation after Day 80, when cotyledonary vessels begin to proliferate. A markedly increased nutrient delivery, to the previously undernourished twin fetuses, could then result in compensatory fetal growth throughout the second half of gestation, resulting in average to above-average birth weights. Although the offspring from nutrient-restricted ewes may be born at similar or greater weights than the offspring from control-fed ewes, it is quite possible that the cardiac ventricular hypertrophy and increased liver weight we observed in fetuses from nutrient-restricted ewes on Day 78 of gestation may lead to hypertension, coronary heart disease, stroke, and/or metabolic disruptions either in neonatal or in adult life. However, further studies will be required to evaluate this hypothesis.
In summary, a constant reduction in energy intake during the critical period of organogenesis and placental development in the pregnant ewe results in markedly smaller fetuses with an accelerated growth of the left and right ventricles of the heart as well as the fetal liver. Further, an enhanced vascular density was observed in the caruncular portion of placentomes associated with twin fetuses recovered from nutrient-restricted ewes. While these compensations in fetal/placental development may be beneficial to fetal survival during an early nutrient restriction, they may prove to be detrimental later in gestation as well as in postnatal life. Additional studies will be required to establish a firm link between these nutrient-associated alterations in conceptus development and metabolic and cardiovascular health of resultant offspring.
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FOOTNOTES |
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Received: 10 October 2002.
First decision: 8 November 2002.
Accepted: 11 February 2003.
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REFERENCES |
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M. J. Zhu, S. P. Ford, W. J. Means, B. W. Hess, P. W. Nathanielsz, and M. Du Maternal nutrient restriction affects properties of skeletal muscle in offspring J. Physiol., August 15, 2006; 575(1): 241 - 250. [Abstract] [Full Text] [PDF]
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 R. C Painter, S. R de Rooij, P. M Bossuyt, T. A Simmers, C. Osmond, D. J Barker, O. P Bleker, and T. J Roseboom Early onset of coronary artery disease after prenatal exposure to the Dutch famine. Am. J. Clinical Nutrition, August 1, 2006; 84(2): 322 - 327. [Abstract] [Full Text] [PDF]
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 D. S. Fernandez-Twinn, S. Ekizoglou, A. Wayman, C. J. Petry, and S. E. Ozanne Maternal low-protein diet programs cardiac beta-adrenergic response and signaling in 3-mo-old male offspring Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R429 - R436. [Abstract] [Full Text] [PDF]
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L. P. Reynolds, J. S. Caton, D. A. Redmer, A. T. Grazul-Bilska, K. A. Vonnahme, P. P. Borowicz, J. S. Luther, J. M. Wallace, G. Wu, and T. E. Spencer Evidence for altered placental blood flow and vascularity in compromised pregnancies J. Physiol., April 1, 2006; 572(1): 51 - 58. [Abstract] [Full Text] [PDF]
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L. P. Reynolds, P. P. Borowicz, K. A. Vonnahme, M. L. Johnson, A. T. Grazul-Bilska, D. A. Redmer, and J. S. Caton Placental angiogenesis in sheep models of compromised pregnancy J. Physiol., May 15, 2005; 565(1): 43 - 58. [Abstract] [Full Text] [PDF]
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K. A. Vonnahme, M. E. Wilson, Y. Li, H. L. Rupnow, T. M. Phernetton, S. P. Ford, and R. R. Magness Circulating levels of nitric oxide and vascular endothelial growth factor throughout ovine pregnancy J. Physiol., May 15, 2005; 565(1): 101 - 109. [Abstract] [Full Text] [PDF]
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J. S. Gilbert, A. L. Lang, A. R. Grant, and M. J. Nijland Maternal nutrient restriction in sheep: hypertension and decreased nephron number in offspring at 9 months of age J. Physiol., May 15, 2005; 565(1): 137 - 147. [Abstract] [Full Text] [PDF]
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 I. C. Mcmillen and J. S. Robinson Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming Physiol Rev, April 1, 2005; 85(2): 571 - 633. [Abstract] [Full Text] [PDF]
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B. A. Costine, E. K. Inskeep, and M. E. Wilson Growth hormone at breeding modifies conceptus development and postnatal growth in sheep J Anim Sci, April 1, 2005; 83(4): 810 - 815. [Abstract] [Full Text] [PDF]
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 L. Zhang Prenatal Hypoxia and Cardiac Programming Reproductive Sciences, January 1, 2005; 12(1): 2 - 13. [Abstract] [PDF]
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J. A Armitage, I. Y Khan, P. D Taylor, P. W Nathanielsz, and L. Poston Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J. Physiol., December 1, 2004; 561(2): 355 - 377. [Abstract] [Full Text] [PDF]
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M.-J. Zhu, S. P. Ford, P. W. Nathanielsz, and M. Du Effect of Maternal Nutrient Restriction in Sheep on the Development of Fetal Skeletal Muscle Biol Reprod, December 1, 2004; 71(6): 1968 - 1973. [Abstract] [Full Text] [PDF]
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M. Du, M. J. Zhu, W. J. Means, B. W. Hess, and S. P. Ford Effect of nutrient restriction on calpain and calpastatin content of skeletal muscle from cows and fetuses J Anim Sci, September 1, 2004; 82(9): 2541 - 2547. [Abstract] [Full Text] [PDF]
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H. Kwon, S. P. Ford, F. W. Bazer, T. E. Spencer, P. W. Nathanielsz, M. J. Nijland, B. W. Hess, and G. Wu Maternal Nutrient Restriction Reduces Concentrations of Amino Acids and Polyamines in Ovine Maternal and Fetal Plasma and Fetal Fluids Biol Reprod, September 1, 2004; 71(3): 901 - 908. [Abstract] [Full Text] [PDF]
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H.-C. Han, K. J. Austin, P. W. Nathanielsz, S. P. Ford, M. J. Nijland, and T. R. Hansen Maternal nutrient restriction alters gene expression in the ovine fetal heart J. Physiol., July 1, 2004; 558(1): 111 - 121. [Abstract] [Full Text] [PDF]
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H. Kwon, G. Wu, C. J. Meininger, F. W. Bazer, and T. E. Spencer Developmental Changes in Nitric Oxide Synthesis in the Ovine Placenta Biol Reprod, March 1, 2004; 70(3): 679 - 686. [Abstract] [Full Text] [PDF]
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H. Kwon, G. Wu, F. W. Bazer, and T. E. Spencer Developmental Changes in Polyamine Levels and Synthesis in the Ovine Conceptus Biol Reprod, November 1, 2003; 69(5): 1626 - 1634. [Abstract] [Full Text] [PDF]
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