Intrauterine Growth Restriction Rats Research Articles

Intrauterine growth restriction increases blood pressure and central pulse pressure measured with telemetry in aging rats

Intrauterine growth restriction (IUGR) is associated with a higher risk of hypertension in adulthood. In Western countries, IUGR is based on uteroplacental dysfunction. We hypothesize that aging augments the increased baseline blood pressure after IUGR and alters the cardiovascular response to acute stress. To evaluate blood pressure during aging in the rat, we used a model of uteroplacental dysfunction (bilateral uterine artery ligation). Blood pressure was measured in male offspring at the ages of 6, 9, and 12 months using telemetry, allowing for unstressed measurements in conscious animals. At 6 and 12 months of age, cardiovascular data were obtained during acute olfactory stress induced by ammonia and subsequent recovery. Rats born after IUGR had lower birth weights (4.6 versus 6.5 g, P < 0.001) and did not completely catch up in weight by 12 months of age (519 versus 567 g, P < 0.01). Systolic blood pressure was significantly higher in IUGR animals at all ages. Pulse pressure (PP) was identical in both groups at the age of 6 months. However, PP increased in the IUGR group with increasing age, unlike the control group, and was significantly higher at 9 and 12 months of age. At the age of 12 months, there was a highly significant negative correlation between birth weight and PP (r = -0.82, P < 0.001). IUGR rats reached a higher peak in systolic blood pressure during stress, and showed a longer period for the raised heart rate to recover after stress. IUGR is associated with raised baseline blood pressure, an increasing PP with age, and an altered stress response.

Pituitary mRNA Expression of the Growth Hormone Axis in the 1‐Year‐Old Intrauterine Growth Restricted Rat

Intrauterine growth restriction (IUGR) is one of the major causes of short stature in childhood. Abnormalities in the growth hormone (GH) axis have frequently been observed in children who are born intrauterine growth restricted and GH treatment is effective to improve final height. However, the way that the GH axis is involved is not fully understood. Previously, when investigating the effect of IUGR on the central somatotrophic axis, a hypothalamic effect was discovered with elevated somatostatin and decreased neuropeptide Y mRNA expression levels, whereas serum GH and insulin-like growth factor I (IGFI) were unaltered. These findings were thought to indicate a hypothalamic alteration of the GH axis due to IUGR, probably to compensate pituitary output, thereby normalising peripheral values of GH and IGFI. Therefore, the present study aimed to evaluate the effect of IUGR on the pituitary GH axis in this rat model. Pups from rats that underwent bilateral uterine artery ligation at day 17 of pregnancy were studied. Pituitary glands were collected from 1-year-old offspring for quantitative measurements of GH, GH-receptor (GH-R), GH-releasing hormone receptor (GHRH-R), somatostatin receptor subtype 2 and 5, IGFI and IGFI receptor mRNA levels using a real-time reverse transcriptase-polymerase chain reaction. In addition, liver GH-R and IGFI mRNA expression levels were measured and a radioimmunoassay was performed to determine serum IGFI levels. In the IUGR rat, levels of pituitary GH, GH-R and GHRH-R relative gene expression (RGE) were increased. No differences were found in the RGE level of all other pituitary growth factors, liver GH-R and IGFI, and serum IGFI concentration between IUGR and control rats. The present data show that intrauterine growth failure leads to changes in the pituitary that might counterbalance the effects found previously in the hypothalamus.

Uteroplacental insufficiency increases p53 phosphorylation without triggering the p53-MDM2 functional circuit response in the IUGR rat kidney

Uteroplacental insufficiency (UPI) leads to intrauterine growth restriction (IUGR), which predisposes infants toward renal insufficiency early in life and increases the risk of kidney-related adult morbidities, such as hypertension. This compromised in utero environment has been demonstrated to impair nephrogenesis, as evidenced by a reduced nephron endowment in humans and in rats rendered IUGR by UPI. Concordantly, we have observed that IUGR rats have increased kidney p53 protein levels associated with increased apoptosis. Several factors can regulate p53 gene expression and activity, including posttranslational modifications and protein-protein interactions in the cell. Among these, two important mechanisms are 1) phosphorylation of the amino terminal serine 15 [phospho-p53 (Ser15)], which increases p53 stability and apoptotic activity, and 2) the murine double-minute (MDM2) functional circuit that limits further p53-induced apoptosis by promoting proteosomal degradation of p53. We hypothesize that UPI induces an increase in phospho-p53 (Ser15) in association with an absent MDM2 response, predisposing the kidney to increased apoptosis. To test our hypothesis, we induced IUGR through bilateral uterine artery ligation of the pregnant rat. UPI significantly increased phospho-p53 (Ser15), as well as ataxia teleangiectasia-mutated kinase/A-T-related kinase and dsDNA-activated protein kinase kinase levels, which induce phosphorylation of p53. In contrast, UPI induced no increase in kidney MDM2 mRNA and protein levels in IUGR pups. We conclude that among multiple mechanisms that affect nephrogenesis, UPI induces an increase in p53 phosphorylation without a corresponding increase in MDM2 expression, and we speculate that this response may contribute to the increased apoptosis previously described in the IUGR kidney.

Glucose metabolic adaptations in the intrauterine growth-restricted adult female rat offspring

We studied glucose metabolic adaptations in the intrauterine growth-restricted (IUGR) rat offspring to decipher glucose homeostasis in metabolic programming. Glucose futile cycling (GFC), which is altered when there is imbalance between glucose production and utilization, was studied during a glucose tolerance test (GTT) in 2-day-old (n = 8), 2-mo-old (n = 22), and 15-mo-old (n = 22) female rat offspring. The IUGR rats exposed to either prenatal (CM/SP, n = 5 per age), postnatal (SM/CP, n = 6), or pre- and postnatal (SM/SP, n = 6) nutrient restriction were compared with age-matched controls (CM/CP, n = 5). At 2 days, IUGR pups (SP) were smaller and glucose intolerant and had increased hepatic glucose production and increased glucose disposal (P < 0.01) compared with controls (CP). At 2 mo, the GTT, glucose clearance, and GFC did not change. However, a decline in hepatic glucose-6-phosphatase (P < 0.05) and fructose-1,6-biphosphatase (P < 0.05) enzyme activities in the IUGR offspring was detected. At 15 mo, prenatal nutrient restriction (CM/SP) resulted in greater weight gain (P < 0.01) and hyperinsulinemia (P < 0.001) compared with postnatal nutrient restriction (SM/CP). A decline in GFC in the face of a normal GTT occurred in both the prenatal (CM/SP, P < 0.01) and postnatal calorie (SM/CP, P < 0.03) and growth-restricted offspring. The IUGR offspring with pre- and postnatal nutrient restriction (SM/SP) were smaller, hypoinsulinemic (P < 0.03), and hypoleptinemic (P < 0.03), with no change in GTT, hepatic glucose production, GFC, or glucose clearance. We conclude that there is pre- and postnatal programming that affects the postnatal compensatory adaptation of GFC and disposal initiated by changes in circulating insulin concentrations, thereby determining hepatic insulin sensitivity in a phenotype-specific manner.

Perturbed skeletal muscle insulin signaling in the adult female intrauterine growth-restricted rat

To determine the molecular mechanism(s) linking fetal adaptations in intrauterine growth restriction (IUGR) to adult maladaptations of type 2 diabetes mellitus, we investigated the effect of prenatal seminutrient restriction, modified by early postnatal ad libitum access to nutrients (CM/SP) or seminutrient restriction (SM/SP), vs. early postnatal seminutrient restriction alone (SM/CP) or control nutrition (CM/CP) on the skeletal muscle postreceptor insulin-signaling pathway in the adult offspring. The altered in utero hormonal/metabolic milieu was associated with no change in basal total IRS-1, p85, and p110beta subunits of PI 3-kinase, PKCtheta, and PKCzeta concentrations but an increase in basal IRS-2 (P < 0.05) only in the CM/SP group and an increase in basal phospho (p)-PDK-1 (P < 0.05), p-Akt (P < 0.05), and p-PKCzeta (P < 0.05) concentrations in the CM/SP and SM/SP groups. Insulin-stimulated increases in p-PDK-1 (P < 0.05) and p-Akt (P < 0.0007), with no increase in p-PKCzeta, were seen in both CM/SP and SM/SP groups. SHP2 (P < 0.03) and PTP1B (P < 0.03) increased only in SM/SP with no change in PTEN in CM/SP and SM/SP groups. Aberrations in kinase and phosphatase moieties in the adult IUGR offspring were initiated in utero but further sculpted by the early postnatal nutritional state. Although the CM/SP group demonstrated enhanced kinase activation, the SM/SP group revealed an added increase in phosphatase concentrations with the net result of heightened basal insulin sensitivity in both groups. The inability to further respond to exogenous insulin was due to the key molecular distal roadblock consisting of resistance to phosphorylate and activate PKCzeta necessary for GLUT4 translocation. This protective adaptation may become maladaptive and serve as a forerunner for gestational and type 2 diabetes mellitus.

Association of Birth Weight with Cardiovascular Parameters in Adult Rats During Baseline and Stressed Conditions

Low birth weight (LBW) due to intrauterine growth restriction (IUGR) in humans is associated with increased blood pressure (BP) in adulthood. In Western countries, IUGR is based on uteroplacental dysfunction. We used an animal model of uteroplacental dysfunction to evaluate this correlation. We hypothesize that IUGR increases baseline BP and alters the BP response to acute stress, which may explain BP differences in previous studies using stressful methods to obtain BP. IUGR was induced by bilateral uterine artery ligation in pregnant Wistar rats according to a modified method of Wigglesworth. BP was measured in the offspring using telemetry, allowing for unstressed measurements in conscious animals. Cardiovascular data were obtained at the age of 12 wk during baseline and acute olfactory stress induced by an ammonia gauze. Rats born after IUGR had a lower birth weight versus controls and did not completely catch up in weight. At baseline, systolic BP (SBP), mean arterial pressure (MAP), and pulse pressure (PP) were elevated in IUGR rats versus controls, by 8, 6, and 5 mm Hg, respectively. There was a strong negative correlation between birth weight and SBP and between birth weight and PP. During acute stress, there was a tendency to reach a higher peak in SBP and to need a longer period to recover in IUGR animals. We conclude that IUGR is associated with increased baseline BP.

55 Is Nephron Number Reduction Sufficient to Explain the Fetal Programming of Hypertension

Introduction: Intrauterine growth restriction (IUGR) is associated with increased risk of cardiovascular and metabolic diseases in adulthood. Nephron number reduction has been proposed as a key mechanism for later hypertension. Aim: To compare the long term effects of two models of IUGR on arterial systolic blood pressure (SBP) and renal function in adult rats. Methods: 3 groups of animals were investigated: group I, controls: offspring of dams fed normal diet (NP, casein 22 %); group II: offspring of dams fed isocaloric low-protein diet (LP, casein 9 %); group III: offspring of dams that received 3 daily intramuscular injections of betamethasone (0.25 mg/kg) on gestational days 17,18, 19 (BET). SBP, glomerular number, and renal function were obtained in 12 months old animals. Results: (mean +/- SEM). Glomerular number was significantly reduced in IUGR rats (38 % in LP rats and 50 % in BET rats vs. controls p<0.05). At 2 months, unlike BET rats, LP rats displayed a significant elevated SBP compared to controls (135 +/- 3, 144 +/- 3, 130 +/- 3 mmHg in groups BET, LP, controls; p<0.05). At 12 months, SBP levels were not significantly different between the groups despite an alteration of Creatinine Clearance in BET rats (3.25 +/-0.2, 4.82 +/-0.4, 4.88+/-0.5, ml/min/kg in groups BET, LP and controls; p<0.05). Conclusion: Despite no differences in birth weight, maternal low protein diet and short course maternal injections of betamethasone have different effects on SBP, renal function and GT in adult rats, while both reduce nephron number. The hypothesis of an inborn nephron deficit associated with single nephron hyperfiltration appears not sufficient to explain the fetal programming of hypertension.

53 Effects of Intrauterine Growth Restriction (IUGR) and Postnatal Catch-Up Growth on Arterial Blood Pressure (BP), Glucose Tolerance (GT) and Renal Func

Introduction: Epidemiological and experimental studies demonstrate that low birth weight is associated with increased risk of arterial hypertension and metabolic diseases in adulthood. Rapid postnatal catch-up growth may constitute an additional risk factor.Aim: To investigate the long term effects of early postnatal overfeeding (OF) after IUGR, on arterial systolic blood pressure (SBP), GT, and renal function in 12 month old, adult rats.Methods: 4 groups of animals were investigated from birth to 12 months: group I, controls: offspring of dams fed normal diet (NP, casein 22 %); group II: offspring of dams fed isocaloric low-protein diet (LP, casein 9 %); group III: postnatal OF (obtained by reduction of litter size); group IV: LP rats exposed to postnatal OF. SBP was measured at 1, 2, 8 and 12 months, glomerular number was determined in newborn pups and renal function (creatinine clearance (CrCl), was assessed at 4 and 12 months. Intraperitoneal glucose tolerance test was performed in 12 months old animals. Data were analyzed by Kruskall-Wallis and Mann-Withney tests.Results: (mean +/- SEM). LP rats offspring had a 20 % birth weight and 38 % glomerular number reduction (p < 0.01). Postnatally OF rats had the higher growth rate during suckling period (p <0.005). Although smaller at birth, LP+OF rats caught up the weight of control offspring within the first postnatal month. Catch-up growth was associated with an elevated SBP from the age of 4 weeks (110 +/-3; 117 +/- 2; 116 +/- 3; 127 +/- 2 mmHg in groups NP, LP, OF, LP+OF rats respectively; p < 0.05), which remained higher in 12 months old LP+OF rats. LP and OF rats displayed a significantly elevated SBP from the age of 2 months in comparison with controls (144 +/- 3; 146 +/-1.6; 130 +/- 3 mmHg, respectively; p < 0.05). But the difference in SBP between LP and controls rats disappeared at the age of 12 months. CrCl decreased with age in LP+OF rats but reached statistical significance in males at 12 months (3.34 +/- 0.2; 4.26 +/-0.3; 4.61+/-1.6; 5.48 +/-1.6 ml/min/kg in LP+OF, LP, OF, controls respectively). At the age of 12 months, fasting glycaemia was significantly elevated in LP+OF rats compared to controls (6.4 vs 5.1 mmol/l). After challenge with a glucose load OF and LP+OF rats had significantly higher 30 min blood glucose levels compared with controls (24+/-1.9; 19+/-1.8; 17 +/-1.2;17+/-0.8 mmol/l in LP+OF, OF, LP, controls respectively; p<0.05).Conclusion: Early catch-up growth in IUGR rats enhances alteration of SBP, glucose tolerance and renal function in adulthood. Long term alteration of renal function seems influenced by gender. Early postnatal overfeeding may amplify single nephron hyperfiltration, and insulin-resistance associated with IUGR, resulting in cardiovascular and metabolic diseases at adulthood.

54 Effects of Intrauterine Growth Restriction and Catch-up Growth on Arterial Blood Pressure, Glucose Tolerance and Renal Function in Adult Rats

Introduction: Low birth weight is associated with increased risk of arterial hypertension and metabolic diseases in adulthood. Rapid postnatal catch-up growth may constitute an additional risk factor. Aim: To investigate the effects of postnatal overfeeding (OF) after intrauterine growth restriction (IUGR) in 12 month old, adult rats. Methods: 4 groups of animals were investigated: group I, controls: offspring of dams fed normal diet (NP, casein 22 %); group II: offspring of dams fed isocaloric low-protein diet (LP, casein 9 %); group III: postnatal OF (obtained by reduction of litter size); group IV: LP rats exposed to postnatal OF. Systolic blood pressure (SBP), glomerular number, renal function, fasting glycaemia and intraperitoneal glucose tolerance test were obtained Results: (mean +/- SEM). Offspring of dams fed LP diet had a 20 % birth weight and 38 % glomerular number reduction (p < 0.01). Catch-up growth was associated with an elevated SBP from the age of 4 weeks (110 +/-3; 117 +/- 2; 116 +/- 3; 127 +/- 2 mmHg in groups NP, LP, OF, LP+OF rats respectively; p < 0.05). But the difference in SBP between LP and controls rats disappeared at the age of 12 months. Creatinine clearance decreased with age in LP+OF rats but reached statistical significance in males at 12 months (3.34 +/- 0.2; 4.26 +/-0.3; 4.61+/-1.6; 5.48 +/-1.6 ml/min/kg in LP+OF, LP, OF, controls respectively). Proteinuria was significantly higher in LP+OF rats than in controls at 4 months. At the age of 12 months, glucose tolerance was significantly altered in OF and LP+OF rats. Conclusion: Early catch-up growth in IUGR rats enhances alteration of SBP, glucose tolerance and renal function in adulthood. Early postnatal overfeeding may amplify single nephron hyperfiltration, and insulin-resistance associated with IUGR, resulting in cardiovascular and metabolic diseases at adulthood.

Uteroplacental insufficiency alters hepatic expression, phosphorylation, and activity of the glucocorticoid receptor in fetal IUGR rats

Uteroplacental insufficiency (UPI) induces persistent changes in hepatic gene expression secondary to altered chromatin dynamics in the intrauterine growth- restricted (IUGR) rat liver. The glucocorticoid receptor (GR) is a transcription factor that when activated can induce changes in chromatin structure. To begin the process of identifying pathways by which IUGR affects chromatin structure, we hypothesized that UPI in the rat induces a significant increase in endogenous glucocorticoids (corticosterone) and increases GR expression and activation. To prove our hypothesis, we induced IUGR through bilateral uterine artery ligation of the pregnant rat. At day 1, UPI significantly increased corticosterone levels and was associated with increased total GR mRNA and protein levels in the liver, as well as increased hepatic phosphorylation of GR serine 211. Moreover, cyclin-dependent kinase 2 (CDK2) cyclinA/CDK2 protein levels, which selectively phosphorylate GR serine 211, were also significantly increased. To assess activity of the GR, we measured protein levels of the transcription factor p53 whose levels are downregulated, at least in part, by active GR. In this study, UPI decreased p53 protein and its downstream target Bax mRNA levels. We conclude that UPI in rats affects GR expression and activity in the liver. We speculate that these alterations early in life may contribute to the changes in chromatin structure and gene expression previously described in the IUGR liver.

Intra‐uterine growth restriction and the programming of left ventricular remodelling in female rats

Epidemiological studies link intra-uterine growth restriction (IUGR) with increased incidence of hypertension and cardiac disease in adulthood. Our rat model of IUGR supports this contention and provides evidence for the programming of susceptibility for hypertension in all offspring. Moreover, in the female offspring only, gross anatomical changes (cardiac ventricle to body ratios) and increased left cardiac ventricular atrial natriuretic peptide (ANP) mRNA levels provide evidence for programming of cardiac disease in this gender. The aim of the current study was to measure changes in cardiac tissue that support remodelling that could be implicated in the initiation of hypertrophy. Adult female rats from our IUGR model and age- and sex-matched controls were killed at 12 weeks of age. Left cardiac ventricles were removed and used for monitoring changes in several key genes, Na+,K+-ATPase beta1 protein expression, cardiomyocyte morphology and contractility as well as citrate synthase and aconitase activities. When compared to controls, female offspring of our IUGR rat model exhibit higher expression (mRNA) of ANP and the atrial isoform of the myosin light chain, lower levels of Na+,K+-ATPase beta1 protein, increased cardiomyocyte depth and volume, increased sarcomere length, diminished cardiomyocyte contractility and lower aconitase activity. Female offspring of our IUGR rat model exhibit changes as adults that are consistent with the onset of cardiac remodelling. The decrease in aconitase activity suggests that oxidative stress may be implicated in this response.

Intra‐uterine Growth Restriction Downregulates the Hepatic Toll Like Receptor‐4 Expression and Function

Maternal starvation is a significant cause of intrauterine growth restriction (IUGR) in the world and increases the risk of infection in the neonate. We examined the effect of maternal starvation on Toll like receptor (TLR)4 expression in hepatic, splenic and intestinal tissues obtained from the adult IUGR offspring of prenatal calorie restricted rats. The hepatic TLR4 protein concentration was undetectable in the IUGR rats that had restricted milk intake during the suckling period (SM/SP; n = 4, p < 0.05) as compared to the normal growth controls (CM/CP; n=4), and access to ad lib milk intake during the sucking period partially corrected the hepatic TLR4 expression (SM/CP; n = 4). IUGR had no effect on the splenic (n = 4) or intestinal (n = 4) TLR4 mRNA levels. In the liver, IUGR led to a 20% increase in baseline tumor necrosis factor (TNF)-α mRNA expression ( p < 0.03) and a 70% increase in interleukin-1β (IL-1β) mRNA expression ( p < 0.008) as compared to the control rats (CM/CP; n = 7). LPS-induced hepatic TNF-α release was significantly higher in SM/SP as compared to CM/CP. We propose that IUGR dysregulates TLR4 expression and function in the offspring, which may help explain the increased risk of Gram-negative sepsis and inflammatory diseases in this population.

Effects of maternal undernutrition during late gestation on the lung surfactant system and morphometry in rats.

Intrauterine growth restriction (IUGR) is associated with reduced lung function during infancy and throughout adulthood. We investigated the effects of maternal undernutrition (50% rations of the control food intake) during the last week of gestation on the pulmonary surfactant system and lung morphometry in postnatal rats. IUGR rats exhibited a significantly lower body weight, lower lung weight, lower lung/body weight ratio, lower lung volume, and lower lung volume/body weight ratio on some postnatal days. IUGR rats had a significantly lower lung saturated phosphatidylcholine and lower plasma corticosterone levels on postnatal d 1 only, and values were comparable between control and IUGR rats in the ensuing weeks. Lung surfactant protein (SP)-A, SP-B, SP-C, and SP-D mRNA expressions were similar between control and IUGR rats. Volume fractions of the alveolar airspace were significantly lower in IUGR rats on postnatal d 7, 14, and 42. Alveolar surface areas were significantly lower in IUGR rats during the study period. The alveolar surface area/body weight ratio reached a peak on postnatal d 7, and values were significantly lower in IUGR rats on postnatal d 1, 14, 28, and 42. We conclude that maternal undernutrition during late gestation decreases lung surfactant lipid levels in the immediate postnatal period and alters the development of lung structure during the postnatal period. Alteration of lung surfactant and structure may be important in the pathogenesis of impaired pulmonary function in IUGR infants and children.

Intrauterine growth restriction in rats is associated with hypertension and renal dysfunction in adulthood.

Epidemiological studies have produced evidence that unfavorable intrauterine environments during fetal life may lead to adverse outcomes in adulthood. We have previously shown that a low-sodium diet, given to pregnant rats over the last week of gestation, results in intrauterine growth restriction (IUGR). We hypothesize that pups born with IUGR are more susceptible to the development of hypertension in adulthood. IUGR fetuses and rats aged 1 wk were characterized for organ growth and renal morphogenesis. The adults (12 wk) were evaluated for weight, systolic blood pressure, activity of the renin-angiotensin-aldosterone system (RAAS), and renal function; hearts and kidneys underwent a histological examination. Brain and cardiac ventricle-to-body ratios were increased in IUGR fetuses compared with age-matched controls, whereas the kidney-to-body ratio was unchanged. Systolic blood pressure was elevated in both IUGR male and female adults. Plasma aldosterone levels were not correlated with increased plasma renin activity. Moreover, urinary sodium was decreased, whereas plasma urea was elevated in both males and females, and creatinine levels were augmented only in females, suggesting a glomerular filtration impairment in IUGR. In our model of IUGR induced by a low-sodium diet given to pregnant rats, high blood pressure, alteration of the RAAS, and renal dysfunction are observed in adult life. Differences observed between male and female adults suggest the importance of gender in outcomes in adulthood after IUGR.

Developmental changes of 3H-labelled μ-opioid receptors in brainstems of intra-uterine growth-restricted rats

The opioid μ-system is involved in brainstem-mediated respiratory control. Infants with intra-uterine growth restriction (IUGR) have more respiratory disorders in the early postnatal period. Using [ 3H]DAGO, a μ-selective ligand, and a computer-based image analysis of autoradiography, we compared the ontogeny and distribution of μ-opioid binding sites in the brainstem of IUGR and control rats in utero (E21), at birth (P0) and on postnatal days 1 (P1), P7, P10, P14 and P21. The ontogeny pattern was found to be similar in both groups. The density of the binding sites, which was low in E21, increased at P0, slightly declined at P1 and remained relatively constant thereafter. The distribution of DAGO-binding sites, also similar in both groups, was heterogeneous and was much denser in the dorsal areas of medulla and pons. In particular, binding sites were highly concentrated in nuclei involved in the cardio-respiratory function. However, DAGO-binding density was higher at all ages (except for P0 and P1) in IUGR than in control rats. Taken together, these results give at least a partial explanation for the effects of IUGR which lowers the Apgar score at birth and raises the incidence of respiratory disorders in infants.

Uteroplacental Insufficiency Alters Expression of Eph A8 in the Brain of Intrauterine Growth Restricted Rats

Uteroplacental Insufficiency Alters Expression of Eph A8 in the Brain of Intrauterine Growth Restricted Rats

Effect of intrauterine growth restriction on blood pressure, glucose tolerance and sympathetic nervous system activity in the rat at 3–4 months of age

Epidemiological studies suggest that intrauterine growth restriction (IUGR) due to maternal undernutrition during pregnancy represents a major risk factor for hypertension and diabetes in adult age. However, placental insufficiency, rather than maternal malnutrition, is the main cause of IUGR in the Western world. We therefore studied the relationship between birth weight and adult blood pressure and glucose tolerance in an established animal model of placental insufficiency. IUGR was induced by uterine artery ligation in pregnant rats and the offspring were studied at 3-4 months of age. In one subgroup of animals (n = 41, birth weight range 3.2-6.6 g) blood pressure was recorded over 72 h using telemetry and hypothalamic tissue levels of noradrenaline was measured. In another subgroup (n = 30, birth weight range 3.0-6.8 g) the activity of the sympathetic nervous system (SNS) was assessed by noradrenaline isotope dilution techniques and glucose tolerance determined by an intravenous glucose load. Adult blood pressure was independent of birth weight Haemodynamic responses of IUGR rats to moderate sound stress was unaltered. In male rats neither SNS activity, hypothalamic noradrenaline concentrations nor glucose tolerance was associated with birth weight In contrast, IUGR in female rats was associated with increased SNS activity, elevated fasting blood glucose as well as lower insulin and higher glucose levels in response to a glucose load. IUGR is not linked to an elevated blood pressure at 3-4 months of age in this model. However, in female rats, IUGR is associated with increased SNS activity and impaired glucose tolerance in adult life.

Increased binding of epidermal growth factor to placental membranes of intrauterine growth restricted fetal rats.

To examine the relationship between nutrient supply and fetal and placental growth, we examined epidermal growth factor (EGF) binding to membranes prepared from placentas of growth-restricted fetal rats. Intrauterine growth retardation was accomplished by unilateral ligation of the uterine artery; fetal rats on the contralateral uterine horn served as controls. Fetal growth restriction was accompanied by decreased placental wt at 19 and 20 day's gestation and significantly decreased placental glycogen content at 20 and 21 days, 30% and 15%, respectively. Placental DNA content and protein/DNA ratios were similar in the growth-restricted and control groups. Specific binding of 125I-EGF was increased in growth-restricted placentas at 19 and 20 days' gestation by 32% and 16%, respectively. 125I-EGF binding at 20-21 days increased linearly with the extent of placental growth restriction. Competitive binding experiments yielded linear Scatchard plots with an increased receptor density in growth-restricted placenta at 19 and 20 days' gestation, 74% and 60%, respectively. Binding affinities for the EGF receptor were similar in the two groups. The increased binding of EGF to membranes prepared from growth-restricted fetal rats may serve to enhance nutrient uptake under conditions of decreased uterine blood flow.