IUGR Offspring Research Articles

442 Awardee Talk: Adaptive Programming of Poor Skeletal Muscle Growth and Metabolism Associated with Heat Stress-Induced Intrauterine Growth Restriction

Abstract Intrauterine growth restriction (IUGR) is associated with reduced β2 adrenergic sensitivity, which contributes to poor postnatal muscle growth and metabolic inefficiency. Thus, our objective was to determine if stimulating β2 adrenergic activity would rescue deficits in muscle growth, body composition, and indicators of metabolic homeostasis in IUGR offspring. Maternal heat stress (40°C, 35% humidity, THI = 85) from d 40 to 95 of gestation was used to produce IUGR lambs. From birth, IUGR lambs received daily IM injections of saline (IUGR; n = 12) or 0.8 μg/kg clenbuterol HCl (IUGR+CLEN; n = 11). Placebo-injected controls (n = 13) were born to pair-fed thermoneutral ewes. Body composition was estimated by ultrasound and bioelectrical impedance analyses (BIA) at d 58. Lambs were catheterized at d 55 and necropsied at d 60. Square-wave hyperglycemic clamps and indirect calorimetry were performed at d 57. Hyperinsulinemic-euglycemic clamps were performed at d 58. Bodyweights were lighter (P ≤ 0.05) for IUGR and IUGR+CLEN lambs than for controls at birth, d 30, and d 60. Average daily gain was less (P ≤ 0.05) for IUGR compared with controls and was intermediate for IUGR+CLEN lambs. BIA-estimated fat-free mass, ultrasound-estimated loin eye area (LEA), actual LEA, and flexor digitorum superficialis (FDS) muscle weight were less (P ≤ 0.05) for IUGR but not IUGR+CLEN lambs than for controls. Semitendinosus from IUGR lambs had less (P ≤ 0.05) β2 adrenoreceptor content, fewer (P ≤ 0.05) proliferating myoblasts, tended to have fewer (P = 0.08) differentiated myoblasts, and had smaller (P ≤ 0.05) muscle fibers than controls. Proliferating myoblasts and fiber size but not β2 adrenoreceptor content or differentiated myoblasts were rescued (P ≤ 0.05) in IUGR+CLEN lambs compared with IUGR lambs. Basal plasma insulin did not differ, but glucose-stimulated insulin secretion was 44% less (P ≤ 0.05) for IUGR lambs than for controls and was intermediate for IUGR+CLEN lambs. Basal and insulin-stimulated hindlimb glucose uptake and basal glucose oxidation did not differ among groups. Insulin-stimulated glucose oxidation was 54% less (P ≤ 0.05) for IUGR lambs but not IUGR+CLEN lambs compared with controls. Ex vivo glucose uptake was 25% less (P ≤ 0.05) for FDS from IUGR and IUGR+CLEN lambs than from controls. Ex vivo glucose oxidation was less (P ≤ 0.05) for FDS and soleus from IUGR lambs compared with controls and was intermediate (P ≤ 0.05) for FDS but not soleus from IUGR+CLEN lambs. Whole-body O2 consumption was 22% less (P ≤ 0.05) for IUGR and IUGR+CLEN lambs than for controls. Whole-body CO2 production was 17% less (P ≤ 0.05) for IUGR but not IUGR+CLEN lambs than for controls. These findings show that IUGR muscle remained responsive to β2 adrenergic stimulation despite reduced β2 adrenoreceptor content, and thus β2 adrenergic pathways may be a strategic target for improving muscle growth, body composition, and metabolic efficiency in IUGR-born offspring.

Abstract 29: Acute Systemic Treatment With Sphingosine -1- Phosphate Receptor 1 Agonist Diminishes Sex-difference In Renal Function Seen In Intrauterine Growth Restricted Mice.

IUGR is a risk factor for the early development of cardiorenal diseases in life. We previously showed that our IUGR mouse model exhibits sex differences in blood pressure (BP) and kidney functions as males have elevated BP and impaired kidney function while females are not. Sphingosine-1-Phosphate Receptor 1 (S1PR1) is reported to be involved in developing and progressing several cardiorenal diseases. We found that acute activation of S1PR1 transiently reduced BP in male IUGR; however, the effects of SIPR1 on renal function in IUGR are still unknown. We hypothesize that S1PR1 plays a role in the sex differences of impaired kidney function in IUGR. Here we investigated the acute effects of a specific S1PR1 agonist (SEW2178) on kidney function in IUGR offspring generated through placental insufficiency. Methods: C57BL IUGR or control offspring were obtained from the Reduced Uterine Perfusion Pressure (RUPP) or sham surgeries on the 13 th day of gestation. At 6 months, nephron number was measured by analyzing kidney histology while Glomerular Filtration Rate (GFR) was measured using FITC-Anulin decay after retroorbital injection. Mice were treated with 3mg/kg SEW2871 i.p before GFR measurement. Results: Both male and female IUGR had a decrease in nephron number compared to same-sex control (371.8± 28.8 vs 284.0± 11.3, P<0.01, male control vs IUGR) and (333.6±13.3 vs 256± 13.0, P<0.05, female control vs IUGR). Furthermore, IUGR impaired kidney function in male but not female mice as indicated by reduced GFR (8.9 ±0.6 vs 13.9±1.1 μL/min/kg BW, P<0.05, IUGR vs control males) and (12.3±0.9 vs 15.9 ±1.9 L/min/kg BW, control females vs IUGR). Administration of SEW2871 diminished the difference of GFR between male control and IUGR (9.5±0.6 vs 9.7±1.1 μL/min/kg BW, P> 0.05 control vs IUGR). While in females, both IUGR and control had a similar response to SEW2178 (7.4±1.0 vs 10.6 ±1.9 μL/min/kg BW, control vs. IUGR). Conclusion: IUGR impairs renal function in male offspring but not in females, indicating sex differences in fetal programming of kidney disease. Male and female IUGR offspring respond differently to acute systemic activation of S1PR1. Further studies are required to investigate the kidney-specific and cell-specific of S1PR1 activation/inhibition.

Intrauterine growth restriction alters nutrient metabolism in the intestine of porcine offspring

BackgroundIntrauterine growth restriction (IUGR) has negative impacts on the postnatal survival, growth and development of humans and animals, with not only on newborns but also adulthood. However, the characteristics for nutrient digestion and absorption in IUGR offspring are still largely unknown. Therefore, the normal birth weight (NBW) and IUGR growing pigs were used in this study to investigate their differences in nutrient utilization, with an expectition for further nutritional optimization of the IUGR offspring during their later life.MethodsTwelve IUGR and 12 NBW growing pigs were fitted with catheters in their portal vein to measure blood flow rate as well as nutrients and metabolites in plasma. The digestibilities of nutrients in different intestinal segments, and bacterial fermentation in the large intestine were examined to reveal the characteristics of nutrients utilization in IUGR versus NBW pigs.ResultsThe rate of portal venous blood flow did not differ beween IUGR and NBW pigs. Plasma concentrations of total cholesterol, triglycerides and glucose were much lower but those of urea were higher in the portal vein of IUGR pigs, compared with the NBW pigs. The ileal digestibility of dry matter, gross energy and starch were lower in IUGR pigs than in NBW pigs. IUGR increased hindgut microbial diversity and bacterial fermentation activity in the caecum. In vitro cross-fermentation of ileal digesta by caecal microbes of NBW and IUGR pigs showed that gas production was much higher for IUGR ileal digesta regardless of the source of caecal inocula.ConclusionIUGR impairs the nutrient digestion and absorption in small intestine, reduces caecal microbial diversity and promotes bacterial fermentation in the large intestine during the growing phase. These findings aid in our understanding of nutrient metabolism in IUGR pigs and provide the basis for future nutritional interventions.

Epigenetic mechanisms involved in intrauterine growth restriction and aberrant kidney development and function.

Intrauterine growth restriction (IUGR) due to uteroplacental insufficiency results in a placenta that is unable to provide adequate nutrients and oxygen to the fetus. These growth-restricted babies have an increased risk of hypertension and chronic kidney disease later in life. In rats, both male and female growth-restricted offspring have nephron deficits but only males develop kidney dysfunction and high blood pressure. In addition, there is transgenerational transmission of nephron deficits and hypertension risk. Therefore, epigenetic mechanisms may explain the sex-specific programming and multigenerational transmission of IUGR-related phenotypes. Expression of DNA methyltransferases (Dnmt1and Dnmt3a) and imprinted genes (Peg3, Snrpn, Kcnq1, and Cdkn1c) were investigated in kidney tissues of sham and IUGR rats in F1 (embryonic day 20 (E20) and postnatal day 1 (PN1)) and F2 (6 and 12 months of age, paternal and maternal lines) generations (n = 6-13/group). In comparison to sham offspring, F1 IUGR rats had a 19% decrease in Dnmt3a expression at E20 (P < 0.05), with decreased Cdkn1c (19%, P < 0.05) and increased Kcnq1 (1.6-fold, P < 0.01) at PN1. There was a sex-specific difference in Cdkn1c and Snrpn expression at E20, with 29% and 34% higher expression in IUGR males compared to females, respectively (P < 0.05). Peg3 sex-specific expression was lost in the F2 IUGR offspring, only in the maternal line. These findings suggest that epigenetic mechanisms may be altered in renal embryonic and/or fetal development in growth-restricted offspring, which could alter kidney function, predisposing these offspring to kidney disease later in life.

258 Deficits in growth, muscle mass, and body composition following intrauterine growth restriction persisted in lambs at 60 d of age but were improved by daily clenbuterol supplementation

Abstract Intrauterine growth restriction (IUGR) reduces neonatal muscle growth and alters body composition in livestock. Our objective was to determine the effect of IUGR on juvenile growth and assess the benefits of treatment with clenbuterol (β2 adrenergic agonist) in IUGR offspring. Heat stress-induced IUGR lambs were born 28% lighter (P &amp;lt; 0.05) than controls. At 60 d of age, unsupplemented IUGR lambs had reduced (P &amp;lt; 0.05) bodyweight (BW), average daily gain, and crown-rump length compared to controls, but clenbuterol-supplemented IUGR lambs did not differ from controls. Crown circumference, body girth, and cannon bone length did not differ among groups. Bioelectrical impedance in live lambs and carcasses estimated that lean mass and mass of multiple muscle groups were reduced (P &amp;lt; 0.05) in unsupplemented IUGR lambs but not clenbuterol-supplemented IUGR lambs compared to controls. Estimated protein, fat, and protein/fat were likewise reduced (P &amp;lt; 0.05) in unsupplemented but not clenbuterol-supplemented IUGR lambs. Loin-eye area in chilled carcasses was 30% smaller (P &amp;lt; 0.05) in unsupplemented IUGR lambs but 19% larger (P &amp;lt; 0.05) in clenbuterol-supplemented IUGR lambs compared to controls. Proximate analysis revealed greater (P &amp;lt; 0.05) fat and reduced (P &amp;lt; 0.05) protein and protein/fat in loin muscles from unsupplemented but not clenbuterol-supplemented IUGR lambs compared to controls. At necropsy, hindlimbs, hearts, and flexor digitorum superficialis muscles tended to be lighter (P ≤ 0.09) and lungs and kidneys were lighter (P &amp;lt; 0.05) in IUGR lambs. Kidney weight was further reduced (P &amp;lt; 0.05) in clenbuterol-supplemented IUGR lambs. Brain/BW tended to be reduced (P ≤ 0.09) and lung/BW and kidney/BW were reduced (P &amp;lt; 0.05) in IUGR lambs, but lung weight and lung/BW were greater (P &amp;lt; 0.05) in clenbuterol-supplemented compared to unsupplemented IUGR lambs. We conclude that poor growth and asymmetric body composition previously observed in IUGR neonates persists in juveniles, but daily treatment with clenbuterol recovered growth and improved body composition in IUGR lambs.

Ouabain regulates kidney metabolic profiling in rat offspring of intrauterine growth restriction induced by low-protein diet

AimsIntrauterine growth restriction (IUGR) can increase the risk of hypertension and kidney disease at adulthood due to fetal programming. In our previous study, we found that supplementation with low concentration of ouabain during pregnancy could restore glomerulus numbers at birth, rescuing kidney development. However, the metabolic pattern of kidney in IUGR offspring and the effect of ouabain have not been evaluated. Main methodsIn this study, based on GC–MS and LC-MS platforms, we used the protein restriction rat model to explore the molecular mechanisms of kidney damage induced by IUGR and the protective effect of ouabain. Key findingsThe results showed that malnutrition could induce IUGR in rat offspring at the 20th gestational day but ouabain treatment could partially reverse the body and kidney weight loss. Ouabain treatment could upregulate arginine, N-acetylornithine and carbamoyl phosphate as well as adenine nucleotide and guanine nucleotide downregulated by low-protein diet. Moreover, six metabolites were identified to be significantly correlated with fetal kidney weight, with 3 metabolites involved in arginine metabolism (arginine, N-acetylornithine, urea) and UDP-glucuronate correlated positively, while lysine and anthranilate correlated negatively. SignificanceThe results suggested that the underlying mechanism of ouabain against renal maldevelopment involved the metabolic regulation, particularly the arginine metabolism, which played an important role in the development of fetal kidney.

Abstract 136: Attenuation of Increased Blood Pressure by Chronic Estrogen Supplementation in Female IUGR Offspring at 12 months of Age is Associated With a Shift Towards ACE2

Low birth weight ( LBW ) women exhibit an earlier age at menopause and a two-fold greater prevalence of hypertension in later life. In a model of LBW induced via placental insufficiency in the rat, female LBW rats develop an increase in blood pressure ( BP ) by 12 months of age. This is associated with persistent estrous that occurs 6 months prior to controls, indicative of early reproductive senescence. Although the underlying mechanisms are unknown, a shift in the hormonal milieu in addition to dysregulation of the renin angiotensin system ( RAS ) are potential contributors to the increase in BP that occurs in women after menopause. The vasoconstrictor arm of the RAS is implicated in increased BP; ACE2 counterbalances this shift towards increased BP. We previously reported that renal ACE2 expression is elevated in female LBW rats that are normotensive in young adulthood; an increase that is not present in female LBW rats in later life. Thus, this study tested the hypothesis that chronic 17β-estradiol ( E2 ) supplementation would reduce BP and shift the balance of the RAS in female LBW rats. Placebo or E2 pellets (1.5mg 17β-estradiol, 60-day release) were implanted at 12 months of age for 6 weeks followed by measurement of BP in conscious, chronically catheterized animals. Kidneys were collected for molecular analysis. BP was significantly increased in placebo-treated LBW relative to placebo-treated Control (134 vs 122 mmHg, respectively, p &lt;0.05); an increase that was abolished by chronic E2 in LBW (116 mmHg, p &lt;0.05). Using Real-Time PCR, cortical ACE2 mRNA expression did not differ between Control or LBW rats. Medullary ACE2 mRNA expression was significantly increased in placebo-treated LBW compared to placebo-treated Controls (1-fold increase; p &lt;0.05). However, following chronic E2, medullary ACE2 mRNA expression was increased to a greater degree in chronic E2-treated LBW rats, almost two-fold higher, relative to chronic E2-treated Control. Therefore, these results suggest that E2 supplementation attenuates increased BP in female LBW rats in a manner that may involve a shift in the RAS towards ACE2 abundance suggesting that ACE2 via chronic E2 may be beneficial in the treatment of increased BP that occurs after reproductive senescence in LBW.

Decreased expression of GLUT4 in male CG-IUGR rats may play a vital role in their increased susceptibility to diabetes mellitus in adulthood.

Rats with intrauterine growth retardation and catch-up growth (CG-IUGR) after birth show increased susceptibility to diabetes mellitus in adulthood. The expression of glucose transporter type 4 (GLUT4) decreases in female IUGR offspring rats with seminutrient restriction during pregnancy. However, the male CG-IUGR rats also display an increased susceptibility to diabetes mellitus in adulthood. Whether there is another factor, besides GLUT4, in male CG-IUGR rat that mediates their susceptibility to diabetes mellitus? The male IUGR rats with catch-up growth were selected as the research objects. CG-IUGR rats had an increased fasting blood glucose level, and increased serum total cholesterol, triglyceride and free fatty acid levels. Glucose tolerance test and insulin tolerance test showed higher glucose levels and much higher insulin levels after a glucose load in CG-IUGR. The mRNA and protein expressions of IRS-2 in liver tissue, and IRS-1 and GLUT4 in skeletal muscle in CG-IUGR rats were down-regulated, but only the GLUT4 down-regulation displayed strong negative correlations with the decreased glucose tolerance capability by Pearson's analysis. The methylation patterns of CpG islands in the promoter regions of IRS-1, IRS-2 and GLUT4 in CG-IUGR rats varied, which was not significantly correlated with their expressions. The male CG-IUGR rats showed decreased glucose tolerant capability, suggesting increased susceptibility to diabetes mellitus in adulthood. The GLUT4 down-regulation may play a vital role in the development of decreased glucose tolerance in male CG-IUGR rats. The methylation modification of the promoter region of GLUT4 does not appear to be involved in its expression.

Short- and long-term effects of maternal perinatal undernutrition are lowered by cross-fostering during lactation in the male rat.

Undernutrition exposure during the perinatal period reduces the growth kinetic of the offspring and sensitizes it to the development of chronic adult metabolic diseases both in animals and in humans. Previous studies have demonstrated that a 50% maternal food restriction performed during the last week of gestation and during lactation has both short- and long-term consequences in the male rat offspring. Pups from undernourished mothers present a decreased intrauterine (IUGR) and extrauterine growth restriction. This is associated with a drastic reduction in their leptin plasma levels during lactation, and exhibit programming of their stress neuroendocrine systems (corticotroph axis and sympatho-adrenal system) in adulthood. In this study, we report that perinatally undernourished 6-month-old adult animals demonstrated increased leptinemia (at PND200), blood pressure (at PND180), food intake (from PND28 to PND168), locomotor activity (PND187) and altered regulation of glycemia (PND193). Cross-fostering experiments indicate that these alterations were prevented in IUGR offspring nursed by control mothers during lactation. Interestingly, the nutritional status of mothers during lactation (ad libitum feeding v. undernutrition) dictates the leptin plasma levels in pups, consistent with decreased leptin concentration in the milk of mothers subjected to perinatal undernutrition. As it has been reported that postnatal leptin levels in rodent neonates may have long-term metabolic consequences, restoration of plasma leptin levels in pups during lactation may contribute to the beneficial effects of cross-fostering IUGR offspring to control mothers. Collectively, our data suggest that modification of milk components may offer new therapeutic perspectives to prevent the programming of adult diseases in offspring from perinatally undernourished mothers.

Prenatal hypoxia causes long‐term retina dysfunction in rats

BackgroundEvidence indicates that prenatal stressors, such as hypoxia, can induce phenotypic changes in the fetus which increase its predisposition to age‐related complications. We hypothesized that aged offspring exposed to prenatal hypoxia would exhibit exacerbated age‐related functional decline of the retina.MethodsFemale Sprague‐Dawley rat offspring (that were maintained at either 11% O2 [hypoxic] or 21% O2 [normoxic] from gestational day (GD)15 to GD21, term=GD22) had their retina function assessed 2 and 14 months of age by electroretinophy (ERG). Anatomy was assessed by immunofluorescence microscopy.ResultsDark‐adapted mixed a‐wave (rod and cone function) and b‐wave (bipolar cell activity) amplitudes were diminished in hypoxic offspring; these effects were most apparent at 14 months. Young and aged hypoxic offspring also had fewer mixed a‐wave threshold responses, and mixed b‐wave responses were markedly reduced in light adapted conditions. Light‐adapted flicker fusion frequency was also reduced in aged hypoxic versus age‐matched normoxic controls. There was no evidence of reduced photoreceptor cell numbers, although there was evidence of glial fibrillary acidic protein (GFAP) accumulation in aged IUGR offspring, providing evidence of photoreceptor damage.ConclusionsPrenatal hypoxia causes both intrinsic and age‐related changes in retina function.

52 EFFECTS ON CARDIAC STRUCTURE IN ADULT RATS WHEN INTRAUTERINE GROWTH RESTRICTION IS COUPLED WITH HYPERGLYCEMIA

Objective: Aim of this study was to examine the effect of type 1 diabetes on myocardial collagen deposition and cardiac function in IUGR rat offspring when blood glucose levels were maintained at either mild or moderate levels. Methods: IUGR was induced in Wistar-Kyoto rats by maternal protein restriction. At 24 weeks of age, diabetes was induced in male IUGR and non-IUGR offspring by streptozotocin injection; insulin was injected daily to maintain blood glucose levels at either a mild level (7-10mmol/L; n = 8 per group) or a moderate level (10-15mmol/L; n = 8 per group). Results: Morphological and echocardiographical analyses of the heart were performed at 32 weeks of age. There was induction of left ventricular hypertrophy in IUGR offspring of 32 weeks of age; this was accompanied by a thicker posterior wall and increased interstitial fibrosis. Induction of hyperglycemia also led to an increase in heart size and myocardial fibrosis. The response to hyperglycemia was not different between IUGR and non-IUGR adult rats however, cardiac fibrosis was greatest when diabetes was combined with IUGR. Conclusion: Tight glycemic control attenuated the adverse effects of hyperglycemia but did not reverse the increased collagen deposition. Exacerbated fibrosis in diabetic IUGR hearts even when glycemia is tightly controlled may lead to long-term cardiac dysfunction.

Abstract 192: Intra-Placental Gene Transfer of Human Insulin-Like Growth Factor-1 Reprograms Fetal Predisposition to Obesity in Intra-uterine Growth Restriction

We have shown that intra placental adenoviral mediated gene transfer of (Ad hIGF1) corrects birth weight in a new surgical mouse IUGR model. Evidence shows that IUGR offspring are predisposed to increased risk of adult diseases. We hypothesized that intraplacental Ad hIGF1 not only restores birth weight in this IUGR model but prevents adult onset obesity through fetal reprogramming Laparotomy was done at day 18 on time pregnant C57BL/6J mice, divided into 3 groups. Control: Sham operated; IUGR: birth weight &lt;10% for gestational age; Treated: IUGR+IGF1; n= 16. Pups were delivered on day 20, cross fostered to surrogate CD1 mice, sorted by gender at 4 weeks and followed up to 24 weeks. Body weight, fat pad weight, fasting serum leptin and food consumption were measured. Data analyzed by Chi-square or ANOVA Compared to SHAM, IUGR significantly reduced birth weight, restored to normal in IUGR+IGF-1 (1.12± .1vs 0.9± .1 vs 1.09± .1 g, p= .001). At 8 weeks, IUGR achieved mean body weight equivalent to SHAM and IUGR+IGF-1. By week 21, regardless of sex, IUGR significantly increased weight (obesity) compared to sham and IUGR+IGF-1 (fig A). Total fad pad weights were significantly higher in IUGR compared to SHAM but were restored to normal in IUGR+IGF1 (fig B). IUGR significantly increased fasting serum leptin, compared to Sham and restored to normal in IUGR+IGF1 ( .6± .4vs 5.7± 1.1 vs .8± .4 pg/ug, p= .01). No difference in food consumption amongst the groups Intra placental gene transfer of Ad hIGF1 corrects birth weight in IUGR mice model and attenuates the risk of postnatal obesity, This support the concept that in utero reprogramming of fetal predisposition to obesity is a novel approch to treatment of IUGR.

Myocardial macronutrient transporter adaptations in the adult pregestational female intrauterine and postnatal growth-restricted offspring

Associations between exponential childhood growth superimposed on low birth weight and adult onset cardiovascular disease with glucose intolerance/type 2 diabetes mellitus exist in epidemiological investigations. To determine the metabolic adaptations that guard against myocardial failure on subsequent exposure to hypoxia, we compared with controls (CON), the effect of intrauterine (IUGR), postnatal (PNGR), and intrauterine and postnatal (IPGR) calorie and growth restriction (n = 6/group) on myocardial macronutrient transporter (fatty acid and glucose) -mediated uptake in pregestational young female adult rat offspring. A higher myocardial FAT/CD36 protein expression in IUGR, PNGR, and IPGR, with higher FATP1 in IUGR, FATP6 in PNGR, FABP-c in PNGR and IPGR, and no change in GLUT4 of all groups was observed. These adaptive macronutrient transporter protein changes were associated with no change in myocardial [(3)H]bromopalmitate accumulation but a diminution in 2-deoxy-[(14)C]glucose uptake. Examination of the sarcolemmal subfraction revealed higher basal concentrations of FAT/CD36 in PNGR and FATP1 and GLUT4 in IUGR, PNGR, and IPGR vs. CON. Exogenous insulin uniformly further enhanced sarcolemmal association of these macronutrient transporter proteins above that of basal, with the exception of insulin resistance of FATP1 and GLUT4 in IUGR and FAT/CD36 in PNGR. The basal sarcolemmal macronutrient transporter adaptations proved protective against subsequent chronic hypoxic exposure (7 days) only in IUGR and PNGR, with notable deterioration in IPGR and CON of the echocardiographic ejection fraction. We conclude that the IUGR and PNGR pregestational adult female offspring displayed a resistance to insulin-induced translocation of FATP1, GLUT4, or FAT/CD36 to the myocardial sarcolemma due to preexistent higher basal concentrations. This basal adaptation of myocardial macronutrient transporters ensured adequate fatty acid uptake, thereby proving protective against chronic hypoxia-induced myocardial compromise.

325 Iugr Affects Long Term Postischemic Neovascularization Capacity

Introduction: Cardiovascular disease is a major cause of premature death. The severity of such diseases has been suggested to result from insufficient angiogenesis processes. Low birth weight is now recognized as a risk factor of mortality for such disease. However, the vascular repair capacity after ischemia in IUGR adult offspring is unknown. Objective: To show how postischemic neovascularization capacity is affected in 12 mo-old adult IUGR rat offspring (maternal gestational low protein diet). Material and Methods: The unilateral hind limb ischemia model by femoral artery resection was used to study the neovascular capacity; the controlateral hind limb served as a reference for each animal. Laser Doppler imaging was used to assess blood flow perfusion in both hind limb after ischemia. Capillary densities of the anterior tibial muscle from both controlateral and ischemic limbs was measured at day 21. Results: After ischemia, IUGR offspring showed marked decreased blood flow in ischemic hind limb from day 1 (-60 % vs -40 % in IUGR and control offspring, p < 0.05). At day 21, while ischemia promoted neovascularization in control offspring (+ 22 %), vascular density was decreased in IUGR ischemic hind limb by 30 % (p < 0.05). Moreover, muscle capillary density of non-ischemic hind limb was higher in IUGR as compared with control offspring (+ 20 %, p < 0.05). Conclusion: Postischemic neovascularization capacity following hind limb ischemia is affected in IUGR adult rat offspring. Angiogenic repair pathways, more than basal capillary density, may be affected in such condition.

Bioavailability of nitric oxide is impaired in hypertensive male IUGR offspring.

Our laboratory utilizes a rat model of placental insufficiency that results in intrauterine growth restriction (IUGR) and hypertension in male IUGR. The purpose of this study was to determine whether impaired nitric oxide (NO) bioavailability contributes to male IUGR hypertension. L‐NAME (nitro‐L‐arginine methyl ester, 10mg/kg/Day) was given in the drinking water for 40 days. Mean arterial pressure (MAP), measured in conscious chronically catheterized rats, was significantly increased in untreated IUGR relative to untreated control (133±3 vs. 122±4 mmHg, P&lt;0.05; IUGR vs. control, respectively). The increase in MAP in response to chronic L‐NAME was greater in control (Ä66 mmHg, 188±12 mmHg, P&lt;0.05 vs. untreated control) as compared to the increase in MAP observed in IUGR (Ä43 mmHg 176±14 mmHg, P&lt;0.05 vs. untreated IUGR). Therefore, these data indicate that control rats were more responsive to NO synthase (NOS) inhibition than IUGR, and that bioavailability of NO may be limited in male IUGR rats. Protein expression of the renal NOS isoforms were significantly reduced upon comparison of male IUGR to male control (eNOS: IUGR indicated 78% of Control; iNOS: IUGR 76% of Control; phosphorylated nNOS IUGR 81% of Control). Thus, these data suggest that a decrease in renal NOS isoform expression may contribute to the reduction in NO bioavailability observed in male IUGR offspring.

“Permanent” dysregulation of central leptin signaling responses to peripheral leptin in programmed obese IUGR offspring

“Permanent” dysregulation of central leptin signaling responses to peripheral leptin in programmed obese IUGR offspring

595: Intrauterine undernutrition and kidney development in a rat IUGR model

Fetal growth restriction has been linked with adult hypertension and renal disease. This may at least in part be a consequence of lower number of nephrons in IUGR offspring. One possipility is that glucocorticoids which are increased in response to IUGR-related stress affect kidney development through Cyclooxygenase-2 (COX-2) and 11beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2). Our objective was to determine the effect of in utero caloric food restriction in rats on kidney gene exrpession of COX-2, 11 beta-HSD2, Mineralocorticoid Receptror (MR) and Glucocorticoid Receptor (GR).

Programmed alteration of hypothalamic leptin and insulin signaling pathways contributes to reduced anorexigenic responses in IUGR offspring

Programmed alteration of hypothalamic leptin and insulin signaling pathways contributes to reduced anorexigenic responses in IUGR offspring

2C-4 Maternal food restriction during pregnancy affects hepatic IGF-1 mRNA and chromatin structure in the adult IUGR offspring

2C-4 Maternal food restriction during pregnancy affects hepatic IGF-1 mRNA and chromatin structure in the adult IUGR offspring

Sensitivity to metabolic signals in late-gestation growth-restricted fetuses from rapidly growing adolescent sheep

Fetal sensitivity to insulin and glucose was investigated during fetal hyperinsulinemic-euglycemic (HI-euG, n = 18) and hyperglycemic-euinsulinemic (HG-euI, n = 12) clamps. Singleton bearing adolescent ewes were fed high (H) or control (C) nutrient intakes to induce compromised or normal placental/fetal size, respectively. Catheters were inserted in the umbilical vein (v), fetal artery, (a) and veins, and studies were conducted between day 126 and 133 of gestation. Umbilical blood flow (UmBF) was determined by the steady-state transplacental diffusion technique using (3)H(2)O, and glucose fluxes were quantified by the Fick principle. For the HI-euG study, fetal glucose utilization was measured at spontaneously occurring fetal insulin concentrations and two additional higher levels, whereas fetal glucose was clamped at the initial baseline level. For the HG-euI study, fetal insulin was suppressed by somatostatin infusion, and fetal glucose utilization was determined at baseline (before somatostatin) glucose concentrations, and at 150 and 200% of this value. Placentome weight (219 vs. 395 g), fetal weight (2,965 vs. 4,373 g), and UmBF (519 vs. 794 ml/min) were lower (P < 0.001) in H than in C groups. Relative to control fetuses, glucose extraction (G[v - a]/G[v] x 100) in the nonperturbed state was higher (21.7 vs. 15.9%) in growth-restricted fetuses despite lower glucose (0.78 vs. 1.05 micromol/ml) and insulin (8.5 vs. 16.9 microU/ml) concentrations (all P < 0.001). During the HI-euG study, total fetal glucose utilization rate increased in response to higher insulin concentrations (65 and 64% in H and C groups). Similarly during the HG-euI study, a twofold increase in glucose supply increased fetal glucose utilization by 41 and 44% in H and C groups, respectively. Throughout both studies, absolute total fetal glucose utilization rates were reduced in H vs. C groups (P < 0.01) but were similar when expressed per kilogram fetus (HI-euG: 34.7, 49.5, and 57.5 in H vs. 34.7, 51.2, and 56.1 micromol.min(-1).kg(-1) in C, HG-euI: 28.7, 35.7, and 40.8 in H vs. 32.9, 34.5, and 43.8 micromol.min(-1).kg(-1) in C). These normal body weight-specific metabolic responses to short-term experimental increases in plasma insulin and glucose in response to chronic IUGR indicate maintained mechanisms of insulin action and glucose uptake/utilization capacity, which, if persistent, might predispose such IUGR offspring to excessive energy deposition in later life.