| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
J Physiol (2003), 547.1, pp. 67-76
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2002.027409
 |
ABSTRACT |
|---|
 TopAbstract IntroductionMethodsResultsDiscussionReferences |
|---|
This study used between-breed embryo transfer in the horse to investigate the effects of maternal size and uterine capacity on fetal growth and postnatal cardiovascular and neuroendocrine functions. Equine embryos were transferred to establish eight Thoroughbred-in-Thoroughbred (TinT), seven Pony-in-Pony (PinP), five Thoroughbred-in-Pony (TinP) and eight Pony-in-Thoroughbred (PinT), pregnancies. Maternal and foal weights and placental microscopic area were measured at birth. At 6 days of postnatal life, arterial blood pressure and heart rate were monitored and blood samples were taken for hormone analysis before, during and after a 10 min period of nitroprusside-induced hypotension. Values for maternal and foal weights and placental area at birth were larger in TinT than in PinP pregnancies (P < 0.05). PinT pregnancies resulted in larger placentae and heavier foals relative to PinP (P < 0.05). TinP had smaller placentae and lighter foals relative to TinT (P < 0.05). Growth-enhanced (PinT) foals showed elevated basal arterial blood pressure and baroreflex threshold, reduced baroreflex sensitivity, diminished plasma catecholamine responses to acute stress, and increased cortisol responsiveness to ACTH. Conversely, growth-restricted (TinP) foals showed no change in basal arterial blood pressure, baroreflex threshold or adrenocortical responsiveness to ACTH, but had enhanced baroreflex sensitivity and augmented plasma catecholamine responses to acute stress. The data show that fetal growth acceleration as well as fetal growth restriction, resulting from between-breed embryo transfer in the horse, leads to altered postnatal regulation of blood pressure and the circulating concentrations of cortisol. These findings suggest that deviations in the pattern and rate of fetal growth both above and below the normal trajectory may influence cardiovascular function in postnatal life.
(Received 12 July 2002; accepted after revision 9 October 2002; first published online 15 November 2002)
Corresponding author D. A. Giussani: Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. Email: dag26{at}cam.ac.uk
|
INTRODUCTION |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Epidemiological studies have shown an association between impaired growth in utero and an increased risk of cardiovascular disease in adults in several human populations of different age, sex and ethnicity (Kolacek et al. 1993; Law & Shiell, 1996; Stein et al. 1996; Rich-Edwards et al. 1997; Leon et al. 1998; Eriksson et al. 1999). These findings have led to the 'fetal origins hypothesis' which proposes that cardiovascular and other diseases arise from adaptations made by the fetus to sub-optimal conditions in utero (Barker, 1998). These adaptations, which include slowing of growth, permanently change the physiology and anatomy of the body and, thereby, increase susceptibility to disease in later life (Godfrey, 1998; Hoet & Hanson, 1999). In the epidemiological studies, the increased risk of adult onset degenerative diseases associated with low birth weight has been linked, particularly, to poor nutrition during pregnancy and early postnatal life (Barker, 2001).
Prenatal nutritional programming of postnatal cardiovascular function has been studied experimentally in a number of species including rats, guinea-pigs, sheep and pigs (Anderson et al. 1980; Persson & Jansson, 1992; Robinson et al. 1994; Harding & Johnston, 1995; Woodall et al. 1996; Langley-Evans et al. 1998; Hoet & Hanson, 1999; Poore et al. 2002). In these studies, nutrient availability to the fetus was restricted either by reducing maternal dietary intake during pregnancy or by altering the size and functional capacity of the placenta, the main source of the fetal nutrient supply (Harding & Johnston, 1995; Hoet & Hanson, 1999). All these methods of reducing fetal nutrient availability retard fetal growth and, in several instances, also lead to adult hypertension (Robinson et al. 2000). The mechanisms linking intrauterine growth retardation to abnormalities in postnatal cardiovascular function remain unknown but may involve changes in the hypothalamic- pituitary- adrenal (HPA) axis of the offspring. Glucocorticoids are known to cause hypertension both before and after birth (Derks et al. 1997; Seckl, 1997) and their secretion in the adult has been shown to be influenced by birth weight and the prenatal nutritional environment (Weinstock et al. 1992; Phillips et al. 2001; Lingas & Matthews, 2001).
In species, such as the pig and the horse, in which placentation occurs over the entire uterine surface (Steven, 1975), the placental supply of nutrients and oxygen to the fetus depends on the size of the uterus which, in turn, is determined by the size of the mother. Experimental studies of breeding reciprocal crosses of Shire and Shetland Ponies and of transferring embryos between small and large breeds of horses and pigs have clearly shown that fetal growth can be determined by the size of the mother and her uterine capacity (Walton & Hammond, 1938; Tischner, 1985, 1987; Wilson et al. 1998; Allen et al. 2002). However, the extent to which this method of altering intrauterine growth affects postnatal function of the cardiovascular system and the HPA axis is unknown. Hence, this study investigated the effects of manipulating fetal growth by embryo transfer between Pony and Thoroughbred mares on cardiovascular and HPA functions in the foal after birth.
|
METHODS |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
All procedures used were in accordance with the UK Animals (Scientific Procedures) Act 1986.
Establishment of pregnancies
Within-breed-mating. Individual mares of two experimental herds (one of Pony and the other of Thoroughbred breeds) were artificially inseminated once during oestrus when alternate-day ultrasonographic examination of their ovaries revealed a dominant preovulatory follicle of > 35 mm diameter (Allen et al. 2002). Mares were inseminated with 5-10 ml of fresh semen collected by artificial vagina from the respective breed stallion. The semen was diluted with an equal volume of skim milk glucose extender containing antibiotics. Each mare was given an ovulation-inducing I.V. injection of human chorionic gonadotrophin (hCG, Chorulon, Intervet Laboratories, Cambridge, UK: 1500 i.u. for Ponies and 3000 i.u. for Thoroughbreds) at the time of insemination and the ovaries were scanned daily thereafter to diagnose ovulation. This occurred between 24 and 48 h after injection of hCG and was confirmed by measurement of plasma progesterone concentration in the mare (Allen et al. 2002). Pregnancy was diagnosed by ultrasonographic examination of the uterus between 11 and 14 days after ovulation (Allen et al. 2002).
Between-breed embryo transfer. Other Pony and Thoroughbred mares in the two herds were examined, treated and had blood samples taken as above, except that they were arbitrarily divided into donor and recipient groups for use in the embryo transfer programme. The donor animals were inseminated at the appropriate time with semen from the stallion of the same breed whereas the recipient animals were not inseminated. On day 7 after ovulation (day 0), the uteri of the donor mares were flushed three times with embryo flushing medium as described by Allen et al. (2002) and the infused medium was recovered by gravity flow through an in-line embryo filter (Em-Com, Immuno Systems, Wisconsin, USA). Most of the medium was allowed to pass through but the final 20 ml was searched for the presence of an embryo. If an embryo was found, it was washed three times in fresh medium before it was transferred non-surgically using a transfer gun (21-inch, 0.5 ml plastic disposable equine transfer gun, Veterinary Concepts, Wisconsin, USA) via the cervix to the uterus of a recipient mare that had ovulated 1-3 days after the donor. Pregnancy was diagnosed ultrasonographically 7-9 days after transfer and monitored thereafter every 2 weeks until ca day 60 of pregnancy.
Within- and between-breed embryo transfer techniques gave rise to four experimental groups of animals: Pony fetuses carried by Pony mares (PinP; n = 7), Thoroughbred fetuses carried by Thoroughbred mares (TinT; n = 8), Thoroughbred fetuses carried by Pony mares (TinP; n = 8) and Pony fetuses carried by Thoroughbred mares (PinT; n = 5).
Postnatal measurements and experiments
All births commenced spontaneously and were supervised. Manual assistance was given occasionally, either during the birth process and/or to help the foal stand up and suckle during the first 24 h after delivery. The placenta was collected as it was expelled from the vagina. All foals were weighed within 30 min after delivery. The total microscopic area of the placenta was calculated by multiplying the surface density of the microcotyledons for each placenta by the volume of the chorionic portion of placenta (Allen et al. 2002). The volume of chorion (Vc) was determined by multiplying the volume of allantochorion (Va) measured by saline displacement at birth by the percentage of allantochorion that was just chorion (Pc/100) obtained histologically on 10 biopsy samples of allantochorion (Allen et al. 2002). The surface density of the microcotyledons (Sv) was determined stereologically as described previously (Allen et al. 2002). The total microscopic area of feto-maternal placental contact (S) in m2 was therefore calculated using the following formula: S = Sv 
Vc, where Vc = Va Pc/100.
At 6 days of age, a 10 min period of acute hypotension was induced by infusion of sodium nitroprusside (50 µg kg-1 min-1 Sigma, Poole, UK). The drug was delivered by infusion via a jugular vein catheter inserted under local anaesthesia (lignocaine, Antigen Pharmaceuticals, Roscrea, Ireland) on the day of birth. Systolic (S) and diastolic (D) blood pressures were measured with an electronic cuff sphygmomanometer (automatic digital blood pressure monitor HEM-705CP, Omron Corporation, Japan) placed around the hind limb of the foal, which was placed in lateral recumbency for the 40-50 min period of the experimental protocol. The electronic sphygmomanometer was validated against a mercury sphygmomanometer. Readings for systolic and diastolic blood pressures, and heart rate (determined via auscultation), were taken at 1 min intervals during and for 10 min before and after the infusion of nitroprusside. Venous blood samples (4 ml) were taken at -10 and -5 min prior to infusion, at 5 and 10 min during infusion, and at 5 and 10 min during recovery for measurement of plasma catecholamines, ACTH and cortisol concentrations. One millilitre of collected blood was dispensed into chilled heparin tubes (2 ml Paediatric Li+/heparin tubes; LIP Ltd, Shipley, UK) containing reduced glutathione (4 nmol per tube) and EGTA (5 nmol per tube) for subsequent catecholamine analysis. The remaining blood was dispensed into K+/EDTA tubes (Paediatric EDTA Tubes; LIP Ltd,) for ACTH and cortisol analyses. All tubes were centrifuged at 3000 g for 4 min at 4 °C. Plasma aliquots were snap-frozen in liquid N2 and were stored at -70 °C until required for hormone analyses.
Calculations
Mean arterial blood pressure [D + (Ï(S - D))] was plotted against mean heart rate and mean pulse interval ((1/heart rate) 60 000 expressed in milliseconds) for assessment of baroreflex sensitivity and threshold. Only values for heat rate, pulse interval and arterial blood pressure within the first 5 min following the onset of nitroprusside infusion were taken into account for the baroreflex analysis to ensure analysis of the rapid neural, and not the delayed endocrine, component of the fetal defence responses to acute hypotension. Baroreflex sensitivity was defined as the slope of the linear regression between mean arterial blood pressure and mean pulse interval. Baroreflex threshold, defined as the mean arterial pressure at which the nitroprusside-induced increase in mean heart rate could first be detected, was determined by eye by three independent investigators without knowledge of the treatment groups.
Endocrine analysis
Plasma concentrations of adrenaline and noradrenaline were measured by high performance liquid chromatography (HPLC) using electrochemical detection (Silver et al. 1987). The samples were prepared by absorption of 250 µl of plasma onto acid-washed alumina and 20 µl aliquots of the 100 µl perchloric acid elutes were injected onto the column. Dihydroxybenzylamine was added as the internal standard to each plasma sample before absorption. The limit of sensitivity for the assay was 20 pg ml-1 for adrenaline and noradrenaline. The interassay coefficients of variation for adrenaline and noradrenaline were 7.3 and 6.2 %, respectively. Plasma concentrations of ACTH and cortisol in plasma were measured by radioimmunoassay (RIA) methods previously validated for use with equine plasma (Rossdale et al. 1982; Silver et al. 1984). Plasma ACTH was measured without extraction using a commercially available double antibody 125I RIA kit (Incstar Ltd, Wokingham, UK). The lower limit of detection for the ACTH assay was between 10 and 25 pg ml-1. The intra- and interassay coefficients of variation were 6.5 and 9.0 %, respectively. The lower limit of detection for the cortisol assay was 1.0-1.5 ng ml-1. The intra- and interassay coefficients of variation were 5.3 and 7.8 %, respectively.
Statistical analysis
Values for all variables are expressed as means ± S.E.M. unless otherwise stated. Comparisons within and between treatment groups were assessed for statistical significance using two-way ANOVA with repeated measures followed by the post hoc Tukey test (SigmaStat; SPSS Science, Chicago, USA). Linear regression and third order polynomial were fitted to the relationships between arterial blood pressure, heart rate and pulse interval. Spearman rank order correlation was used to determine the linear relationship between arterial blood pressure and pulse interval and between plasma ACTH and cortisol. Comparisons between the slopes and intercepts of linear regressions were conducted according to Armitage & Berry (1994). For all statistical comparisons, significance was accepted when P < 0.05.
|
RESULTS |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Weights at birth and basal cardiovascular function
PinP and TinT pregnancies produced foals with birth weights similar to those previously reported for normal Ponies and Thoroughbreds (Platt, 1984). The weights of the mares and foals and the total microscopic area of the placenta were significantly higher at birth in TinT than in PinP pregnancies (Fig. 1). However, PinT pregnancies yielded a placenta with a greater total microscopic area and a larger foal relative to PinP pregnancies. Conversely, TinP pregnancies yielded a placenta with a smaller total microscopic area and a lighter foal relative to TinT pregnancies (Fig. 1). Analyses of the data by two-way ANOVA using the maternal and fetal genome as factors showed significant effects of maternal and fetal genotypes on the weights of the mares and foals and the total microscopic area of the placenta at birth (P < 0.05), and greater weights and placental areas at birth were associated with a Thoroughbred genome, whether of maternal or fetal origin. At 6 days of postnatal age, PinT foals had significantly higher basal mean arterial blood pressure relative to all other groups (Fig. 1). In contrast, basal heart rate in the 6-day-old foals was similar in all four groups (Fig. 1).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 1. Measurements at birth Values are means ± S.E.M. for the weights of the mare and foal, the total microscopic area of the placenta, and for the basal mean arterial blood pressure (MAP), heart rate and baroreflex threshold in the foal at 6 days of age. Significant differences are (P < 0.05): a, PinP vs. TinT; b, vs. fetal genotype control; c, vs. all (two-way repeated measures ANOVA). | ||
Cardiovascular responses to acute hypotension
Intravenous treatment with sodium nitroprusside produced falls in mean arterial blood pressure and increases in heart rate which were of similar magnitude in the foals of all four groups (Fig. 2). PinT foals had significantly higher baroreflex threshold relative to all other groups (Fig. 1). When heart rate was plotted against mean arterial blood pressure during baseline and the first 5 min of acute hypotension, PinP and TinT pregnancies had similar baroreflex function curves (Fig. 3A), and the slope of the linear relationship between pulse interval and mean arterial blood pressure was not different between the two groups (Fig. 3B). However, TinP foals had a steep baroreflex function curve and PinT had a shallow baroreflex function curve (Fig. 3A). Therefore, analysis of the slopes of the linear relationship between pulse interval and mean arterial blood pressure in these groups revealed a significant difference in the slopes of the relationship between growth-restricted foals (TinP) and growth-enhanced foals (PinT; Fig. 3B; P < 0.05).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 2. Cardiovascular responses to acute hypotension in the newborn foal Values are means ± S.E.M. for minute averages of arterial blood pressure and heart rate before, during and after a 10 min period of acute hypotension (bar) induced by I.V. treatment of the foal with sodium nitroprusside. | ||
 |
View larger version [in this window] [in a new window] |
|
|
Figure 3. Baroreflex function in the newborn foal Values are means ± x and y S.E.M. for minute averages of mean arterial blood pressure and heart rate (A) or mean arterial blood pressure and pulse interval (B) before and during the first 5 min of acute hypotension in the newborn foal. Trend lines were plotted using third order polynomial (A) or linear (B) regression. Comparisons between the slopes and intercepts of linear regressions were conducted according to Armitage & Berry (1994). | ||
Endocrine responses to acute hypotension
Basal plasma concentrations of noradrenaline, adrenaline, ACTH and cortisol were not different in all groups of foals (Table 1). Analyses of the data by two-way ANOVA using the maternal and fetal genome as factors showed significant effects of the fetal genotype on the basal plasma concentrations of noradrenaline (P < 0.05). Acute hypotension elicited significant increments from baseline in plasma noradrenaline and adrenaline concentrations in PinP, but not TinT foals (Fig. 4A). However, when TinP foals were subjected to acute hypotension, their mean plasma catecholaminergic response was significant and of similar magnitude to that measured in PinP foals (Fig. 4B). Conversely, in PinT foals, the mean plasma catecholamine response to acute hypotension was insignificant and of similar magnitude to that measured in TinT foals (Fig. 4B).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 4. Plasma catecholamine response to acute hypotension in the newborn foal Values are mean ± S.E.M. change from baseline for plasma noradrenaline and adrenaline concentrations before, during and after acute hypotension (bar) in PinP and TinT foals (A) and PinT and TinP foals (B). Significant differences are: a, P < 0.05: baseline vs. hypotension; b, P < 0.05: PinP vs. TinT or PinT; c, P < 0.05: TinP vs. PinT (two-way repeated measures ANOVA). | ||
Acute hypotension elicited significant and similar increments from baseline in plasma ACTH and cortisol in PinP and TinT foals (Fig. 5A). Whilst the magnitude of the increment from baseline in plasma ACTH during hypotension was also similar in TinP foals, it was significantly smaller in PinT foals compared to all groups (Fig. 5B). Conversely, whilst the magnitude of the increment from baseline in plasma cortisol during hypotension was similar in TinP relative to PinP and TinT foals, it was significantly greater compared to all groups in PinT (Fig. 5B). Therefore, whilst the slopes of the linear relationships between mean plasma ACTH and mean plasma cortisol levels during the experimental protocol were similar in PinP, TinT and TinP foals, the slope of this relationship was significantly steeper in PinT compared to all other groups (Fig. 5C; P < 0.05).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 5. Pituitary-adrenocortical response to acute hypotension in the newborn foal Values are mean ± S.E.M. change from baseline for plasma ACTH and cortisol concentrations before, during and after acute hypotension (bar) in PinP and TinT foals (A) and TinP and PinT (B) foals. C, the relationship between plasma ACTH and cortisol (means ± x and y S.E.M.) for all groups. Significant differences are: a, P < 0.05: baseline vs. hypotension or recovery; b, P < 0.05: PinT vs. all (two-way repeated measures ANOVA). | ||
|
DISCUSSION |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study is the first to demonstrate that manipulating fetal growth both above and below the genetic potential alters postnatal cardiovascular and pituitary-adrenal function in the horse. Fetal growth was manipulated by altering placental area through embryo transfer between large and small breeds in a species in which uterine size directly affects the potential surface area for placentation. Growth-enhanced foals, resulting from pregnancies in which Pony embryos were carried by Thoroughbred mares, showed increased basal arterial blood pressure and baroreflex thereshold, reduced baroreflex sensitivity, diminished plasma catecholamine responses to acute hypotension, and enhanced adrenocortical responsiveness to ACTH. Conversely, growth-restricted foals, resulting from pregnancies in which Thoroughbred embryos were carried by Pony mares, showed no change in basal arterial blood pressure, baroreflex threshold or in adrenocortical responsiveness to ACTH, but showed enhanced baroreflex sensitivity and augmented plasma catecholamine responses to acute nitroprusside-induced hypotension.
Cardiovascular function in the offspring
The 'fetal origins hypothesis' proposes that postnatal cardiovascular dysfunction in the offspring originates from adaptations that the fetus makes when it is undernourished (Barker, 1998). Indeed, the international effort addressing this hypothesis has repeatedly demonstrated associations between intrauterine growth restriction and elevated postnatal basal arterial blood pressure both in human populations (Kolacek et al. 1993; Law & Shiell, 1996; Stein et al. 1996; Rich-Edwards et al. 1997; Barker, 1998; Leon et al. 1998; Eriksson et al. 1999) and in studies in animal models in which fetal growth was impaired by experimental manipulation (Robinson et al. 1994; Harding & Johnston, 1995; Ozanne et al. 1996; Woodall et al. 1996; Langley-Evans et al. 1998; Hoet & Hanson, 1999). The data presented in the current study show that growth-enhanced foals have a higher basal arterial blood pressure than all other groups. Therefore, these data suggest that it may not be fetal growth restriction per se that is associated with the onset of degenerative diseases in adulthood, but that deviations in the pattern and rate of fetal growth during gestation above and below the normal trajectory may increase the risk of cardiovascular and metabolic diseases in later life.
The arterial baroreflex maintains blood pressure homeostasis, and sustained alterations in basal blood pressure are accommodated by changes in baroreflex threshold and sensitivity. Permanent changes in the characteristics of the arterial baroreflex may contribute to the development of hypertension in later life (Korner, 1989). In the current study, changes in basal blood pressure and its reflex control are apparent in both growth-restricted and growth-enhanced foals. Growth-enhanced foals resulting from Pony in Thoroughbred pregnancies show an increased threshold of the cardiac baroreflex to accommodate their elevated resting arterial blood pressure. Additional data suggest changes in the gain or sensitivity of the sympathetic component of the arterial baroreflex, such that the slope of the linear relationship between blood pressure and pulse interval was steepest in the growth-restricted foals and shallowest in the growth-enhanced foals. Changes in plasma noradrenaline and adrenaline during the acute hypotensive challenge also support enhanced and reduced neuroendocrine sympathetic drives in growth-restricted and growth-enhanced foals, respectively. Increased neuroendocrine sympathetic drive to cardiac 
1-adrenoreceptors may have contributed to the faster positive chronotropic response to acute hypotension in growth-restricted foals. Conversely, reduced neuroendocrine sympathetic drive to cardiac 1-adrenoreceptors may explain, in part, the slower increase in heart rate in response to acute hypotension in growth-enhanced foals.
Pituitary-adrenal function in the offspring
A large number of clinical and experimental studies have shown that the association between impaired growth in utero with hypertension in postnatal life is also coupled to altered regulation of the HPA axis. For example, human adults whose birth weight was low show greater rates of urinary glucocorticoid secretion (Clark et al. 1996), elevated basal circulating concentrations of cortisol (Phillips et al. 2001) and enhanced adrenocortical responsiveness to ACTH (Reynolds et al. 1999). In addition, the offspring of pregnant ewes, which were undernourished in early gestation, showed altered pituitary and adrenal responsiveness to exogenous and endogenous stimuli in the fetal and postnatal periods (Hawkins et al. 1999, 2000, 2001; Hoet & Hanson, 1999; Edwards et al. 2001; Edwards & McMillen, 2002). In some of these studies, the enhanced pituitary- adrenal responsiveness was associated with a higher resting arterial blood pressure in lambs (Hoet & Hanson, 1999). Numerous other studies have shown that exposure of the human (Kari et al. 1994; Doyle et al. 2000), sheep (Dodic et al. 1998, 1999; Gatford et al. 2000), rat (Benediktsson et al. 1993; Lindsay et al. 1996; Gardner et al. 1997, 1998; Langley-Evans et al. 1998) or guinea-pig (Dean & Matthews, 1999) fetus to increased glucocorticoid concentration, either by exogenous treatment, or by elevating endogenous steroid bioactivity secondary to inactivation of placental 11-hydroxysteroid dehydrogenase, can be associated with impaired fetal growth and postnatal hypertension. Combined, these studies either suggest that enhanced activity of the HPA axis is a final common pathway linking impaired fetal growth and postnatal cardiovascular dysfunction, or that enhanced activity of the HPA axis and altered control of arterial blood pressure simply reflect parallel tracking of programmed changes in these systems by adverse intrauterine conditions. The data reported in this study show that growth-enhanced foals, rather than growth-restricted ones, have enhanced adrenocortical responsiveness to ACTH. This again suggests that it may not be fetal growth restriction secondary to adverse intrauterine conditions per se, but rather deviations in the pattern and rate of fetal growth during gestation above and below the normal trajectory, that may be associated with cardiovascular and pituitary-adrenal dysfunction in later life. Nevertheless, coupling of enhanced activity of the pituitary-adrenal axis, elevated basal arterial blood pressure and modifications in its reflex control also exist in this experimental model of alterations in fetal growth.
In summary, this study reported that fetal growth acceleration as well as fetal growth restriction, resulting from between-breed embryo transfer in the horse, lead to altered postnatal regulation of blood pressure and adrenal function. These findings expand on the Barker hypothesis to suggest that deviations in the pattern and rate of fetal growth both above and below the normal trajectory may predispose to cardiovascular disease in adulthood.
|
REFERENCES |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
| Allen WR, Wilsher S, Turnbull C, Stewart F, Ousey J, Rossadale PD & Fowden AL (2002). Influence of maternal size on placental, fetal and postanatal growth in the horse. I. Development in utero. Reprod 123, 445-453 | |
| Anderson GD, Ahokas RA, Lipshitz J & Dilts PV Jr (1980). Effect of maternal dietary restriction during pregnancy on maternal weight gain and fetal birth weight in the rat. J Nutr 110, 883-890 | [Medline] |
| Armitage P , & Berry G (1994). Further analyses of straight-line data. In Statistical Methods in Medical Research, pp. 292-305. Blackwells, Oxford | |
| Barker DJP, (1998). Mothers, Babies, and Disease in Later Life. Churchill Livingstone, Edinburgh | |
| Barker DJP, (2001). The malnourished baby and infant. Br Med Bull 60, 69-88 | [Abstract/Full Text] |
| Benediktsson R, Lindsay RS, Noble J, Seckl JR & Edwards CR (1993). Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 341, 339-341 | [Medline] |
| Clark PM, Hindmarsh PC, Shiell AW, Law CM, Honour JW & Barker DJ. (1996). Size at birth and adrenocortical function in childhood. Clin Endocrinol 45, 721-726 | |
| Dean F , & Matthews, SG (1999). Maternal dexamethasone treatment in late gestation alters glucocorticoid and mineralocorticoid receptor mRNA in the fetal guinea pig brain. Brain Res 846, 253-259 | [Medline] |
| Derks JB, Giussani DA, Jenkins SL, Wentworth RA, Visser GHA, Padbury JF & Nathanielsz PW (1997). A comparative study of the cardiovascular, endocrine and behavioural effects of betamethasone and dexamethasone administration to fetal sheep. J Physiol 499, 217-226 | [Abstract] |
| Dodic M, May CN, Wintour EM & Coghlan JP (1998). An early prenatal exposure to excess glucocorticoid leads to hypertensive offspring in sheep. Clin Sci 94, 149-155 | [Medline] |
| Dodic M, Peers A, Coghlan JP & Wintour M (1999). Can excess glucocorticoid, predispose to cardiovascular and metabolic disease in middle age? Trends Endocrinol Metab 10, 86-91 | [Medline] |
| Edwards LJ, Coulter CL, Symonds ME & McMillen IC (2001). Prenatal undernutrition, glucocorticoids and the programming of adult hypertension. Clin Exp Pharmacol Physiol 28, 938-941 | [Medline] |
| Edwards LJ , & McMillen IC (2002). Impact of maternal undernutrition during the periconceptional period, fetal number, and fetal sex on the development of the hypothalamo-pituitary adrenal axis in sheep during late gestation. Biol Reprod 66, 1562-1569 | [Abstract/Full Text] |
| Eriksson JG, Forsen T, Tuomilehto J, Winter PD, Osmond C & Barker DJ (1999). Catch-up growth in childhood and death from coronary heart disease: longitudinal study. Br Med J 318, 427-431 | [Abstract/Full Text] |
| Gardner DS, Jackson AA & Langley-Evans SC (1997). Maintenance of maternal diet-induced hypertension in the rat is dependent on glucocorticoids. Hypertension 30, 1525-1530 | [Abstract/Full Text] |
| Gardner DS, Jackson AA & Langley-Evans SC (1998). The effect of prenatal diet and glucocorticoids on growth and systolic blood pressure in the rat. Proc Nutr Soc 57, 235-240 | [Medline] |
| Gatford KL, Wintour EM, De Blasio MJ, Owens JA & Dodic M (2000). Differential timing for programming of glucose homoeostasis, sensitivity to insulin and blood pressure by in utero exposure to dexamethasone in sheep. Clin Sci 98, 553-560 | [Medline] |
| Godfrey KM, (1998). Maternal regulation of fetal development and health in adult life. Eur J Obst Gynaecol Reprod Biol 78, 141-150 | |
| Harding JE , & Johnston BM (1995). Nutrition and fetal growth. Reprod Fertil Dev 7, 539-547 | [Medline] |
| Hawkins P, Hanson MA & Matthews SG (2001). Maternal undernutrition in early gestation alters molecular regulation of the hypothalamic-pituitary-adrenal axis in the ovine fetus. J Neuroendocrinol 13, 855-861 | [Medline] |
| Hawkins P, Steyn C, McGarrigle HH, Saito T, Ozaki T, Stratford LL, Noakes DE & Hanson MA (1999). Effect of maternal nutrient restriction in early gestation on development of the hypothalamic-pituitary-adrenal axis in fetal sheep at 0. 8-0.9 of gestation. J Endocrinol 163, 553-561 | [Medline] |
| Hawkins P, Steyn C, McGarrigle HH, Saito T, Ozaki T, Stratford LL, Noakes DE & Hanson MA (2000). Effect of maternal nutrient restriction in early gestation on responses of the hypothalamic-pituitary-adrenal axis to acute isocapnic hypoxaemia in late gestation fetal sheep. Exp Physiol 85, 85-96 | [Medline] |
| Hoet JJ , & Hanson MA (1999). Intrauterine nutrition: its importance during critical periods for cardiovascular and endocrine development. J Physiol 514, 617-627 | [Abstract/Full Text] |
| Kari MA, Hallman M, Eronen M, Teramo K, Virtanen M, Koivisto M & Ikonen RS (1994). Prenatal dexamethasone treatment in conjunction with rescue therapy of human surfactant: a randomized placebo-controlled multicenter study. Pediatrics 93, 730-736 | [Abstract] |
| Kolacek S, Kapetanovic T & Luzar, V (1993). Early determinants of cardiovascular risk factors in adults. Acta Paediatr 82, 377-382 | [Medline] |
| Korner PI, (1989). Baroreceptor resetting and other determinants of baroreflex properties in hypertension. Clin Exp Pharmacol Physiol Suppl 5, 45-64 | |
| Langley-Evans SC, Gardner DS & Welham SJM (1998). Intrauterine programming of cardiovascular disease by maternal nutritional status. Nutrition 14, 39-47 | [Medline] |
| Law CM , & Shiell AW (1996). Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens 14, 935-941 | [Medline] |
| Leon DA, Lithell HO, Vagero D, Koupilova I, Mohsen R, Berglund L, Lithell UB & McKeigue PM (1998). Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15000 Swedish men and women born 1915-29. Br Med J 317, 241-245 | [Abstract/Full Text] |
| Lindsay RS, Lindsay RM, Edwards CR & Seckl JR (1996). Inhibition of 11-beta-hydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in the offspring. Hypertension 27, 1200-1204 | [Abstract/Full Text] |
| Lingas RI , & Matthews SG (2001). A short period of maternal nutrient restriction in late gestation modifies pituitary-adrenal function in adult guinea pig offspring. Neuroendocrinology 73, 302-311 | [Medline] |
| Ozanne SE, Smith GD, Tikerpae J & Hales CN (1996). Altered regulation of hepatic glucose output in the male offspring of protein-malnourished rat dams. Am J Physiol 270, E559-564 | [Medline] |
| Persson E , & Jansson T (1992). Low birth weight is associated with elevated adult blood pressure in the chronically catheterized guinea pig. Acta Physiol Scand 145, 195-196 | [Medline] |
| Phillips DI, Walker BR, Reynolds RM, Flanagan DE, Wood PJ, Osmond C, Barker DJP & Whorwood CB (2001). Low birth weight predicts elevated plasma cortisol concentrations in adults in 3 populations. Hypertension 35, 1301-1306 | [Abstract/Full Text] |
| Platt H, (1984). Growth of the equine fetus. Equine Vet J 16, 247-252 | [Medline] |
| Poore KR, Forhead AJ, Gardner DS, Giussani DA & Fowden AL (2002). The effects of birth weight on basal cardiovascular function in pigs at 3 months of age. J Physiol 539, 969-978 | [Abstract/Full Text] |
| Reynolds RM, Bendall HE, Walker BR, Wood PJ, Phillips DIW & Whorwood CB (1999). Increased activity of the hypothalamo-pituitary-adrenal (HPA) axis: A link between impaired fetal growth and the insulin resistance syndrome. Proceedings of the 81st Annual Meeting of the Endocrine Society, p. 362 (abstract) | |
| Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA, Willett WC, Hennekens CH (1997). Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. Br Med J 315, 396-400 | [Abstract/Full Text] |
| Robinson JS, Moore VM, Owens JA & McMillan IC (2000). Origins of fetal growth retardation. Eur J Obstet Gynecol Reprod Biol 92, 13-19 | [Medline] |
| Robinson JS, Owens JA & Owens PC (1994). Fetal growth and fetal growth retardation. In Textbook of Fetal Physiology, ed. Thorburn GD & Harding R, pp. 83-94. Oxford University Press, New York | |
| Rossdale PD, Silver M, Ellis L & Frauenfelder H (1982). Response of the adrenal cortex to tetracosactrin (ACTH1-24) in the premature and full-term foal. J Reprod Fertil Suppl 32, 545-553 | [Medline] |
| Seckl JR, (1997). Glucocorticoids, feto-placental 11-hydroxy-steroid dehydrogenase type 2 and the early life origins of adult disease. Steroids 62, 89-94 |
[Medline] |
| Silver M, Fowden AL, Knox J, Ousey JC, Franco R & Rossdale PD (1987). Sympathoadrenal and other endocrine responses to hypoglycaemia in the young foal. J Reprod Fertil Suppl 35, 607-614 | [Medline] |
| Silver M, Ousey JC, Dudan FE, Fowden AL, Knox J, Cash RSG & Rossdale PD (1984). Studies on equine prematurity 2: Postnatal adrenocortical activity in relation to plasma adrenocorticotrophic hormone and catecholamine levels in term and preterm foals. Equine Vet J 16, 278-285 | [Medline] |
| Stein CE, Fall CH, Kumaran K, Osmond C, Cox V & Barker DJ (1996). Fetal growth and coronary heart disease in south India. Lancet 348, 1269-1273 | [Medline] |
| Steven DH, (1975). Anatomy of the placental barrier. In Comparative Placentation, ed. Steven DH, pp. 25-57. Academic Press | |
| Tischner M, (1985). Embryo recovery from Polish-pony mares and preliminary observations on foal size after transfer of embryos to large mares. Equine Vet J Suppl 3, 96-98 | |
| Tischner M, (1987). Development of Polish-pony foals born after embryo transfer to large mares. J Reprod Fertil Suppl 35, 705-709 | |
| Walton A , & Hammond J (1938). The, aternal effects on growth and conformation in Shire horse-Shetland pony crosses. Proc R Soc Lond B Biol Sci 125, 311-335 | |
| Weinstock M, Matlina E, Maor GI, Rosen H & McEwen BS (1992). Prenatal stress selectively alters the sensitivity of the hypothalamic-pituitary-adrenal system in the female rat. Brain Res 595, 195-200 | [Medline] |
| Wilson ME, Biensen NJ, Youngs CR & Ford SP (1998). Development of Meishan and Yorkshire littermate conceptuses in either a Meishan or Yorkshire uterine environment to day 90 of gestation and to term. Biol Reprod 58, 905-910 | [Abstract] |
| Woodall SM, Johnston BM, Breier BH & Gluckman PD (1996). Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring. Pediatr Res 40, 438-443 | [Abstract] |
Acknowledgements
The authors are grateful to Mr Eric Sear, Mr Paul Hughes and Mr Peter Bircham for assistance with the experimental procedures and to Mr Malcolm Bloomfield for the biochemical analysis. The project was supported by the Horserace Betting Levy Board and the Thoroughbred Breeders' association. D.A.G. is a Fellow of The Lister Institute for Preventive Medicine, UK.
This article has been cited by other articles:
|
|
 |
|
  D. S. Gardner To be or not to be ... hypertensive: That is the question J. Physiol., October 1, 2008; 586(19): 4581 - 4581. [Full Text] [PDF]
|
|
|
|
 |
|
 D. A Leon Commentary: The development of the Ounsteds' theory of maternal constraint--a critical perspective Int. J. Epidemiol., April 1, 2008; 37(2): 255 - 259. [Full Text] [PDF]
|
|
|
|
 |
|
 D S Gardner, P J Buttery, Z Daniel, and M E Symonds Factors affecting birth weight in sheep: maternal environment Reproduction, January 1, 2007; 133(1): 297 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
A L Fowden and A J Forhead Endocrine mechanisms of intrauterine programming Reproduction, May 1, 2004; 127(5): 515 - 526. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
