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1 Department of Physiology, The University of Melbourne, Victoria 3010 and 2 St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia 3065
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Evidence implicates pivotal roles for parathyroid hormone-related protein (PTHrP) in stimulating cell growth and differentiation, placental calcium transport, and placental vasodilatation. As spontaneously hypertensive rat (SHR) fetuses are growth restricted compared with those of its normotensive control, the Wistar Kyoto (WKY) rat, we examined intrauterine PTHrP and total and ionic calcium concentrations in these rats. Fetal plasma PTHrP concentrations, but not total calcium concentrations, were lower in the SHR compared with WKY (P < 0.05). SHR placental concentrations of PTHrP were lower than in WKY (P < 0.03) and failed to show the increase observed in WKY near term (P < 0.05). PTHrP concentrations in amniotic fluid from SHR were not raised near term and were lower compared with WKY (P < 0.0005). The increased ionic calcium concentrations in amniotic fluid in the WKY near term (P < 0.05) were not detected in the SHR. Thus SHR fetal plasma, placental, and amniotic fluid PTHrP concentrations were reduced and associated with fetal growth restriction. We suggest that PTHrP may play a role in the etiology of both growth restriction during pregnancy and hypertension later in life.
parathyroid hormone-related protein; pregnancy; intrauterine growth restriction; amniotic fluid; placenta; fetus
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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INTRAUTERINE GROWTH RESTRICTION (IUGR), which affects 5% of human fetuses, contributes significantly to perinatal morbidity and mortality. Recent studies suggest that a predisposition to adult cardiovascular disease is associated with low body weight and high placental weight at birth (2). It has been proposed that in utero programming of adult hypertension is associated with the development of IUGR (22). Furthermore, it has been suggested that cardiovascular alterations occur in fetal life and are progressively amplified from the newborn into adult life (1, 22). The mechanisms by which the intrauterine environment mediates these actions are not known. Pregnancies complicated by intrauterine growth restriction are characterized by poor placentation, impaired placental blood flow, increased vascular resistance, and placental dysfunction (20, 37). Hypertension during human pregnancy is also characterized by abnormal placentation, impaired placental blood flow, and placental dysfunction, which are thought to contribute to the limited placental transfer of nutrients and oxygen that may lead to fetal growth restriction (37). Given that hypertension and IUGR in both rats and humans share some similar pathophysiological features (abnormal calcium homeostasis and impaired placental function), these conditions may be due to altered roles of parathyroid hormone-related protein (PTHrP) in modulating epithelial growth and differentiation, placental calcium transport, and/or placental vascular tone.
PTHrP is produced by, and has important physiological roles in, reproductive, gestational, and fetal tissues (32, 40). In humoral hypercalcemia of malignancy, lactation, and in fetal life, PTHrP can act in a classical endocrine fashion (32, 40). The presence of PTHrP and its PTH/PTHrP receptor in many human fetal tissues and in human gestational tissues, including amnion, placenta, and myometrium (6, 7, 11, 14, 32, 40), also indicates potential autocrine and paracrine functions. Furthermore, we and others (6, 11) demonstrated a significant upregulation of PTHrP mRNA and protein in human amnion and human amniotic fluid (39) at term compared with preterm, at a time when fetal growth and calcium transfer to the fetus are maximal. In the rat, PTHrP has been implicated in uterine contractility and is present in maternal uterine epithelium and myometrial and decidual cells (3, 8, 38), whereas little is known regarding PTHrP content in rat gestational tissues and amniotic fluid.
Both PTHrP and its PTH/PTHrP receptor are essential for fetal development. PTHrP-deficient mice, generated by partial PTHrP gene deletion and homologous recombination, die at birth due to severe skeletal dysplasia and have a reduced maternal-fetal calcium gradient (17, 19). Furthermore, mice with homologous deletion of the PTH/PTHrP receptor gene are growth restricted and die midgestation (21). During pregnancy, PTHrP may act in an autocrine, paracrine, or endocrine fashion by stimulating epithelial cell growth and differentiation (23) and placental calcium transport (5, 19, 32), relaxing uterine smooth muscle (8, 38), and vasodilating fetal-placental vessels (26, 27). Many of these actions are modulated directly or indirectly by calcium.
The spontaneously hypertensive rat (SHR) of the Okamoto strain is an inbred strain exhibiting spontaneous, genetically determined hypertension whose etiology has many similarities to human essential hypertension. The SHR rat fetus is underweight, and placental weight is greater late in gestation compared with the normotensive Wistar Kyoto (WKY) (9, 10, 24). Amniotic fluid volume and composition are also altered in the SHR (10). Because of the vital roles of PTHrP, we hypothesized that suppressed intrauterine PTHrP levels would result in reduced placental blood flow and calcium transport to the fetus and contribute to the development of IUGR. The aims of this study were to investigate the role of PTHrP in normal rat pregnancy and those complicated by maternal hypertension and IUGR by quantifying fetal and maternal plasma, amniotic fluid, and gestational tissue PTHrP concentrations as well as fetal and maternal plasma and amniotic fluid total and ionic calcium concentrations.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental protocol. Virgin female SHR and WKY rats, 10-16 wk old, were obtained from the Biological Research Laboratory (Austin Hospital, Heidelberg, Australia) and kept in plastic cages of three or four rats each in a temperature-controlled room at 22-26°C with lighting from 0600 to 1800. They were mated with a breeder of the same strain after vaginal smears in the morning indicated that they were in proestrus and presumably in estrus on the night of mating. The presence of sperm in the vaginal smear the following morning was taken as day 1 of pregnancy. Systolic blood pressure was measured by an indirect, tail-cuff method using a programmed electrosphygmomanometer with a pneumatic pulse transducer (PE-300, Narco Bio-System, Houston, TX) on day 1 of gestation and on the day before killing. This study has the ethical approval of The University of Melbourne's Animal Experimentation Ethics Committee.
On the mornings of days 16, 20, and 21 of pregnancy, rats were anesthetized intraperitoneally with pentobarbital sodium (Nembutal; Boehringer Ingelheim, Sydney, Australia; 150 mg/kg body wt). There were 8-17 rats/group at each age. The uterus was exteriorized and weighed, and embryonic sacs were separated from the uterus and also weighed. Fetal and maternal blood were obtained by cardiac puncture. Because of the small fetal size, fetal blood was not obtained at 16 days of gestation. Amniotic fluid was aspirated with a 27-gauge needle. Amniotic fluid from every third fetus was collected into aprotinin [0.4 trypsin inhibitor unit (TIU)/ml; Sigma, St. Louis, MO]; all other amniotic fluid samples were untreated. There was insufficient amniotic fluid volume at 21 days of gestation for sampling. Amniotic fluid and plasma samples were frozen in liquid nitrogen and stored at
40°C until analyzed.
Placenta and fetal membranes were separated and weighed individually,
and fetal weight was measured. Amniotic fluid volume was derived by
subtracting placental, fetal membrane, and fetal weights from total sac
weight. Placenta, fetal membranes, and uterine tissue samples from
days 20 and 21 of pregnancy were frozen in liquid
nitrogen and stored at 40°C until assayed.
Protein extraction and DNA and protein assays.
Samples of frozen gestational tissues (1.0 g) at 20 and 21 days of
pregnancy were homogenized for 20 s at 24,000 rpm in 5 ml acetic
acid (1 M) using previously established techniques (6). Duplicate 500-µl aliquots of the homogenate were removed for DNA assay. The remaining homogenate was incubated for 2-3 h at 4°C and centrifuged at 20,000 g for 15 min at 4°C. The
supernatant was then dialyzed against 5 liters deionized water for
22-26 h at 4°C using Spectra-Por 3 dialysis tubing (molecular
weight 6,000-8,000, Cole Palmer, Niles, IL), as previously
described (6). The extract was aliquoted and stored at
20°C for PTHrP radioimmunoassay. Tissue DNA concentrations were
determined using a modified diphenylamine method, as previously
described (6).
PTHrP and calcium measurements. Plasma, amniotic fluid, and tissue concentrations of PTHrP were quantified by a sensitive NH2-terminal radioimmunoassay that does not recognize PTH (15). The radioimmunoassay uses a polyclonal goat antiserum against synthetic PTHrP-(1---40) and recombinant PTHrP-(1---84) as standard. The detection limit is 2 pM, and intra- and interassay coefficients of variation are 4.8 and 13.6%, respectively. Amniotic fluid PTHrP concentrations in each litter (from at least 2 amniotic fluid sacs per litter) were averaged to give one value per litter. Total and ionic calcium concentrations were determined using a Beckman Synchron CX-5 Clinical System (Beckman Coulter, Fullerton, CA) and using ion selective electrodes (Ciba-Corning model 644, Medfield, MA), respectively, from one amniotic fluid sac from each litter and from fetal (total calcium concentrations only) and maternal plasma. At 16 days of gestation there was not sufficient volume of amniotic fluid to measure total calcium concentrations.
Statistical analysis. Homogeneity of variance was analyzed using Bartlett's test. Data were analyzed by two-way analysis of variance (SPSS-X, SPSS). Differences across the stages of pregnancy were determined by post hoc Tukey's test, and differences between strains at each age were determined with a t-test. Data are presented as means ± SE, and P < 0.05 was taken as statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Blood pressures and tissue weights.
Paternal blood pressure and maternal blood pressure at mating and on
the day before postmortem were significantly higher in SHR than WKY for
all age groups (P < 0.0005; Table
1). There was no significant difference
between blood pressure measured at the different stages of
pregnancy. There were no significant differences in maternal
weight, litter sizes, or uterine weight between WKY and SHR at any
gestational age (Table 1). Total amniotic sac weight (fetus, placenta,
amniotic fluid, and fetal membranes) was significantly lower in SHR
than WKY at 16 and 20 but not 21 days of gestation (P < 0.001; Table 1). Uterine and total amniotic sac weight increased
with advancing gestation for both WKY and SHR (P < 0.05; Table 1). Placental weight in the SHR was significantly lower at
16 days and significantly higher at 21 days compared with WKY
(P < 0.001; Table 1). Placental weight of the WKY
increased from 16 to 20 days of gestation, whereas in the SHR it
increased progressively from 16 to 20 and from 20 to 21 days of
gestation (P < 0.001; Table 1). Fetal membrane weight
for the WKY increased significantly from 16 to 20 and 21 days of
gestation with no difference between days 20 and 21 (P < 0.0005; Table 1). In the SHR, fetal membrane weight increased
significantly from 16 to 20 days and from 20 to 21 days
(P < 0.0005). At 16 and 20, but not 21 days of
gestation, fetal membrane weight was significantly lower for SHR
compared with WKY (P < 0.0005; Table 1).
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Fetal and maternal plasma and amniotic fluid PTHrP and total and
ionic calcium concentrations.
SHR fetal plasma PTHrP concentrations (91.4 ± 10.9 pM) were significantly lower than WKY (113.3 ± 6.0 pM) at
20 days of gestation (P < 0.05; see Fig.
4A). Fetal plasma PTHrP concentrations were significantly
greater than those in maternal plasma (P < 0.0001). In
the normotensive WKY, amniotic fluid PTHrP concentrations increased from 6.1 ± 0.3 pM at 16 days to 10.3 ± 0.6 pM at 20 days of
gestation (P < 0.0005; Fig.
3A). This gestational age
increase was not seen in the SHR between 16 and 20 days of gestation
(Fig. 3A). Furthermore, amniotic fluid PTHrP concentrations
were significantly lower in the SHR compared with the WKY at both 16 (SHR: 4.6 ± 0.6 pM; P < 0.01) and 20 days of
gestation (SHR: 6.0 ± 0.7 pM; P < 0.0005; Fig.
3A). In addition, amniotic fluid PTHrP content
(concentrations corrected for volume) was significantly lower at both
16 and 20 days of gestation for the SHR compared with the WKY
(P < 0.005). Pregnant maternal plasma PTHrP
concentrations were not altered by strain or by age and were not
different from nonpregnant values (WKY 6.9 ± 0.3 pM; SHR 8.0 ± 0.4 pM; Table 1).
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PTHrP tissue concentrations.
There was no significant difference between WKY and SHR in PTHrP tissue
concentrations corrected for DNA concentrations in uterus, placenta, or
fetal membranes at 20 days of gestation. At 21 days of gestation, SHR
placental PTHrP concentrations were significantly lower than WKY
(P < 0.03; Table 2) and
failed to show the increase seen in WKY (P < 0.05)
between 20 and 21 days of gestation. At 20 days of gestation, uterine
PTHrP concentrations were significantly greater than placental and
fetal membrane (P < 0.05), which were not different
from each other for both WKY and SHR. In the WKY, at 21 days of
gestation, placental PTHrP concentrations were significantly greater
than both uterine and fetal membrane concentrations (P < 0.05). In contrast, at 21 days of gestation, SHR uterine PTHrP
concentrations were significantly greater than fetal membrane
(P < 0.05) and placental PTHrP concentrations were
comparable to uterine and fetal membrane PTHrP concentrations.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The data presented here demonstrate that fetal plasma, placental, and amniotic fluid PTHrP concentrations are significantly reduced in the SHR compared with the WKY. The deficiency in PTHrP may contribute to the compromised fetal growth and development observed in the SHR. The evidence to date strongly supports the suggestion that small babies who have a large placenta are predisposed to many adult diseases, including hypertension and diabetes (2). Paternal and maternal blood pressures were significantly higher in SHR than WKY, with no differences across the gestational ages studied. There were no significant differences in maternal weight, litter sizes, or uterine and total sac weight between WKY and SHR. Our finding that the hypertensive SHR fetus is growth restricted both at preterm and term gestations is consistent with our previous work (9, 10) and that of others (24). Recently, using embryo transfer techniques, we demonstrated that the reduced fetal weight in the SHR occurs independently of either maternal genetics, hypertension, altered electrolyte, or hormonal factors (9). These studies indicate that the SHR represents an appropriate model to study the role of the intrauterine environment and fetal growth restriction, independent of maternal hypertension and without surgical, endocrine, or nutritional intervention. Furthermore, the growth-restricted SHR has a significantly lower fetal/placental weight ratio than the normotensive WKY near term (9, 10, 24). The SHR's placental weight continues to rise toward term and is significantly higher compared with the WKY at term. Consistent with other studies (9, 10), we also report that amniotic fluid volume is reduced at term in the WKY, whereas this reduction in volume is not found in the SHR.
For the first time, we demonstrated that fetal plasma PTHrP concentrations are reduced in association with growth restriction in the SHR compared with the WKY. A novel observation has also been that in both WKY and SHR, fetal plasma PTHrP concentrations are at least 10-fold higher than maternal plasma and amniotic fluid values, indicating fetal production, possibly from the placenta, parathyroids, or other fetal tissues (32, 40). Furthermore, pregnant maternal plasma PTHrP concentrations are not different from nonpregnant values. These high fetal plasma PTHrP concentrations suggest important physiological role(s) in fetal life. There is controversy regarding human umbilical cord PTHrP concentrations, with some studies reporting similar concentrations to maternal values (30), whereas others cite fetal PTHrP concentrations greater than maternal values (31). A novel observation is that at 20 days of gestation in both WKY and SHR, total calcium concentrations in fetal plasma are significantly lower than in maternal plasma. In human pregnancies, total and ionic calcium concentrations are maintained relatively constant throughout gestation, with fetal calcium concentrations being greater than maternal (18). In contrast to the human data and consistent with our rat data, in late rat pregnancy, decreases in maternal total and ionic calcium concentrations with a significant fetal hypocalcemia relative to maternal plasma (13) may be the result of large losses to the fetal skeleton as indicated by the large rise of fetal calcium content near term (34). Furthermore, larger rat litter sizes are correlated with lower maternal calcium concentrations near term in response to the increased fetal demand (4). Consistent with these observations, we report no differences in litter number or maternal plasma total and ionic calcium concentrations between WKY and SHR. The high fetal PTHrP concentrations in the WKY and SHR may represent an attempt to mobilize fetal calcium across the placenta from fetal circulation to other fetal compartments to compensate for the relative fetal hypocalcemia compared with their mothers. The significantly lower fetal PTHrP concentrations in the SHR may suggest that the SHR fetus is less able to compensate for the fetal hypocalcemia, and the reduced intrauterine PTHrP may contribute to the development of the fetal growth restriction.
The present study demonstrates that placental and amniotic fluid PTHrP concentrations in the normotensive WKY rat increase near term as demonstrated in the human (6, 39). In the SHR, however, placental PTHrP concentrations do not increase toward term, and amniotic fluid PTHrP shows only a modest significant increase toward term. Furthermore, WKY rat amniotic fluid PTHrP concentrations at 20 days of gestation are similar to those found in human amniotic fluid at an equivalent gestational stage (36 wk) (39). However, because of insufficient amniotic fluid volume at 21 days of gestation it is not possible to confirm the large increase closer to term as that observed in the human (39). At term, the size of the intrauterine environment has grown considerably and it is possible that amnion PTHrP mRNA expression and content may be modulated by intrauterine occupancy-induced stretch and hence increased at term, as has been shown in other tissues including the myometrium (32). In support of this suggestion, our studies indicate that amniotic fluid PTHrP concentrations and content from the growth-restricted SHR were significantly lower than WKY at both 16 and 20 days of gestation and did not display the normal increase near term. The mechanism(s) by which amniotic fluid PTHrP concentrations increase at term remain uncertain. There were no significant differences in uterine or fetal membrane PTHrP concentrations between WKY and SHR. The increase in placental PTHrP in the WKY was paralleled by an increase in amniotic fluid ionic calcium concentrations toward term, which was not evident in the SHR. Defects in calcium homeostasis and cellular calcium levels are believed to play a role in the development of IUGR as well as hypertension (33, 35). As a major fetal source of calcium by active transport across the placenta from the mother, the placenta plays a dominant role in fetal calcium homeostasis. Disturbances in maternal or intrauterine calcium homeostasis, therefore, may impact on fetal calcium homeostasis. Thirty to forty percent of all low birth weight infants have neonatal hypocalcemia (33), and calcium transfer to the growth-retarded rat fetus is reportedly reduced (28). Total ionic calcium concentrations in maternal plasma were significantly higher at term in the WKY but not the SHR, which is consistent with previous reports (18, 25). These gestational alterations in maternal calcium concentrations were not associated with any changes over gestation in maternal PTHrP concentrations.
PTHrP mRNA expression and concentrations are reported to be much higher in human amnion than in choriodecidua or placenta at preterm and term (6, 11, 14). In parallel to trends in human amniotic fluid, human amnion PTHrP expression and concentrations increase dramatically at term compared with preterm, and the data suggest that human amniotic fluid PTHrP is amnion derived (6) and not derived from fetal urine (11, 39), but this may not be the case in the rodent. In the WKY, uterine PTHrP tissue concentrations were greater than placental and fetal membranes at 20 but not at 21 days of gestation, whereas uterine tissue concentrations were greater than placental and fetal membranes at both ages in the SHR. In contrast to data obtained in the human (6), PTHrP concentrations in the fetal membranes were not greater than that in the placenta. In the rat, it is possible that uterine, placental, fetal membrane, and fetal PTHrP all contribute to amniotic fluid PTHrP. This study was unable to determine whether gestational tissues earlier in gestation were altered in association with growth restriction of the fetus. Furthermore, the regulation of expression and release of PTHrP in the various gestational tissues may be species specific. Thus the significant increase in placental and amniotic fluid PTHrP at term suggests important physiological roles in modulating fetal, placental, and uterine functions in normal rodent pregnancies. This is further supported by the PTHrP and PTH/PTHrP receptor gene knockout studies that clearly identify PTHrP as essential for normal fetal development and survival (17, 21).
The physiological roles of PTHrP in the fetus and amniotic fluid have yet to be clearly defined. Consequences of reduced fetal plasma, placental, and amniotic fluid PTHrP and in the SHR near term may be reflected in reduced placental calcium transport (5, 19) and vasodilatation (26, 27), thus contributing to the reduced fetal growth at a time when growth is maximal. Lower SHR fetal plasma PTHrP could also reduce growth and/or differentiation of placental tissue, blood vessels, epithelial cells and bone (16, 40), placental calcium transport (5, 19), and vasodilatation (26, 27). Furthermore, swallowing of amniotic fluid, reabsorption of amniotic fluid into the fetal circulation, and bathing of the fetus in amniotic fluid presents PTHrP to many fetal organs and gestational tissues. Studies have also implicated a role for PTHrP in the development and/or maintenance of hypertension in the SHR (12, 40). Experimental hypertension induced by angiotensin II infusion and high salt diet has been shown to increase PTHrP mRNA expression in the adult heart and aorta (36). Furthermore, angiotensin II-induced PTHrP gene expression is impaired in SHR aortic smooth muscle cells (12). The elevated blood pressure in the SHR is associated with a compensatory increase in PTHrP mRNA expression and content in the aorta (29). Thus PTHrP-induced cardiovascular adaptations may be programmed in fetal life with amplification later in life (22).
Perspectives
Reductions in fetal plasma, placental, and amniotic fluid PTHrP concentrations in the SHR may contribute to the etiology and consequences of its growth restriction during pregnancy. Furthermore, these alterations in PTHrP content may act in an autocrine or endocrine fashion to alter intrauterine calcium homeostasis. Given that the intrauterine environment is believed to be important to the programming of hypertension later in life, we suggest that PTHrP may be a significant in utero modulator of fetal growth and development and subsequently blood pressure at maturity. The programming of hypertension may involve PTHrP-induced fetal cardiovascular adaptations and PTHrP-induced fetal growth restriction.| |
ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge the continuing support of Professor T. J. Martin and the technical assistance of Kathy Koutsis, Suzanne Koerner, and Tanya Bradney. We thank Angela Gibson and Professor Geoffrey Tregear from the Howard Florey Institute of Experimental Physiology and Medicine for measuring total calcium.
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FOOTNOTES |
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This study was supported by an Australian Research Council Small Grant (to M. E. Wlodek), Ian Potter Foundation Grant (to M. E. Wlodek), National Heart Foundation Grant (to M. E. Wlodek and R. Di Nicolantonio), and a National Health and Medical Research Council of Australia Program Grant (to J. M. Moseley and P. W. M. Ho).
Address for reprint requests and other correspondence: M. E. Wlodek, Dept. of Physiology, The Univ. of Melbourne, Victoria, Australia 3010 (E-mail: m.wlodek{at}physiology.unimelb.edu.au).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 1 November 1999; accepted in final form 28 January 2000.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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) and spontaneously hypertensive (SHR; 
)
rat (means ± SE). Fetal body weight increased significantly and
progressively over gestation for both strains (P < 0.0005). At each gestational age, SHR fetuses were significantly growth
restricted compared with WKY fetuses (P < 0.01).
Fetal/placental weight ratio increased significantly and progressively
over gestation for both strains (P < 0.0005). At 20 and 21 days of gestation, fetal/placental weight ratio of SHR fetuses
was significantly lower compared with WKY fetuses (P < 0.0009). Significant differences between strains at any age are
indicated by * (P < 0.05), and data values across the
ages for a given strain that share a common letter are not
significantly different from one another (WKY in lowercase and SHR in
uppercase letters; P < 0.05).
