Effect of restriction of placental growth on expression of IGFs in fetal sheep: relationship to fetal growth, circulating IGFs and binding proteins

1995 ◽  
Vol 146 (1) ◽  
pp. 23-34 ◽  
Author(s):  
K L Kind ◽  
J A Owens ◽  
J S Robinson ◽  
K J Quinn ◽  
P A Grant ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fetal Growth ◽  
Fetal Weight ◽  
Ribonuclease Protection Assay ◽  
Fetal Blood ◽  
Fetal Sheep ◽  
Fetal Tissues ◽  
Arterial Blood ◽  
Igf I ◽  
Igfbp 3

Abstract To determine whether tissue production of the IGFs is altered when fetal growth is retarded, IGF-I and -II mRNAs were measured in tissues of fetal sheep subjected to placental restriction and the relationships between IGF gene expression, circulating IGF protein and fetal growth were examined. The majority of potential placental attachment sites were surgically removed from the uterus of 12 non-pregnant ewes to restrict placental size in a subsequent pregnancy. Blood and tissues were collected at 121 days of gestation (term=150) in 12 fetuses with restricted placental size and eight normal fetuses. IGF-I and IGF-II mRNA was detected by solution hybridization/ribonuclease protection assay in placenta and all fetal tissues studied. IGF-I mRNA was most abundant in skeletal muscle and liver and IGF-II mRNA was highest in kidney and lung. Restriction of placental size reduced fetal weight by 17% and reduced the pO2 (18%) and glucose concentration (23%) of fetal blood. Placental restriction also reduced IGF-I mRNA in fetal muscle (P<0·002), lung (P<0·05) and kidney (P<0·01) but had no significant effect on IGF-II mRNA in any tissue. IGF-I mRNA in fetal liver, kidney and skeletal muscle correlated positively with the concentration of IGF-I protein in fetal blood (P<0·01). There was no relationship between the concentration of IGF-II protein in fetal blood and IGF-II mRNA in any fetal tissue examined. The concentration of IGF-binding protein-3 (IGFBP-3) in fetal arterial blood plasma measured by RIA correlated positively with fetal weight and with plasma IGF-I. This study shows that restriction of placental growth in sheep reduces circulating levels of IGF-I and IGFBP-3 in the sheep fetus and reduces the capacity of the fetus to produce IGF-I at a number of tissue sites. Altered production of IGF-I, but not IGF-II, by fetal tissues may contribute to retarded fetal growth. Journal of Endocrinology (1995) 146, 23–34

Circulating insulin-like growth factors-I and -II and substrates in fetal sheep following restriction of placental growth

1994 ◽  
Vol 140 (1) ◽  
pp. 5-13 ◽  
Author(s):  
J A Owens ◽  
K L Kind ◽  
F Carbone ◽  
J S Robinson ◽  
P C Owens
Keyword(s):  
Growth Factors ◽  
Blood Glucose ◽  
Fetal Growth ◽  
Fetal Liver ◽  
Liver Weight ◽  
Fetal Weight ◽  
Fetal Sheep ◽  
Arterial Blood ◽  
Igf I ◽  
Insulin Like Growth Factors

Abstract To determine the relationship between placental delivery of oxygen and glucose, circulating insulin-like growth factors (IGFs) and fetal growth, the effect of variable restriction of placental growth was determined in sheep in late gestation. Arterial blood was obtained via indwelling catheters at 120 and 127 days of gestation, prior to necropsy at 130 days to measure fetal and placental weights. Plasma was acidified and subjected to size-exclusion high-performance liquid chromatography at pH 2·8 to dissociate and separate IGFs from their binding proteins. The acid-dissociated IGF fraction was analysed by sensitive and highly specific radioligand assays for IGF-I and IGF-II, previously defined using ovine IGFs. Fetal weight and blood pO2 and glucose at 120 and 127 days of gestation correlated positively with placental weight. Plasma IGF-I was positively associated with fetal weight and fetal liver weight, and with blood pO2 and glucose at both ages. Plasma IGF-II levels also correlated positively with fetal weight, fetal liver weight and with blood glucose and pO2, but only at 127 days of gestation. In the most severely growth-retarded fetal sheep, blood glucose and pO2 and plasma IGF-I were significantly reduced when compared with normal fetuses at 120 days. All decreased further by 127 days of gestation as did plasma IGF-II in severely growth-retarded fetal sheep compared with normal fetuses. These observations are consistent with the hypothesis that both IGF-I and IGF-II are chronically regulated by oxygen and nutrition in utero and mediate part of the influence of placental supply of substrate over fetal growth. Journal of Endocrinology (1994) 140, 5–13

scholarly journals Effects of acute hypoxemia on insulin-like growth factors and their binding proteins in fetal sheep

2006 ◽  
Vol 263 (6) ◽  
pp. E1151-E1156 ◽  
Author(s):  
H. S. Iwamoto ◽  
M. A. Murray ◽  
S. D. Chernausek
Keyword(s):  
Fetal Growth ◽  
Recovery Period ◽  
Fetal Blood ◽  
Fetal Sheep ◽  
Oxyhemoglobin Saturation ◽  
Subsequent Recovery ◽  
Factor I ◽  
Igf I ◽  
Vascular Catheters ◽  
Insulin Like Growth Factors

It has been proposed that insulin-like growth factor I (IGF-I) regulates fetal growth and differentiation. Plasma IGF-I concentrations correlate positively with fetal nutrient availability and newborn birth weights. To explore the hypothesis that hypoxemia decreases fetal growth by decreasing fetal IGF-I availability, we instrumented 14 fetal sheep with vascular catheters. At least 4 days after surgery, 10 fetuses were made acutely hypoxemic by infusing nitrogen into the maternal trachea for 3 h. Fetal blood oxyhemoglobin saturation decreased from 53 +/- 6 (SD) to 31 +/- 9%. Concomitantly, plasma IGF-I concentrations decreased from 91 +/- 11 to 67 +/- 10 ng/ml and IGF-I binding protein-1 concentration increased significantly, as assessed by ligand and Western blot analysis. Fetal IGF-I concentrations remained below control values throughout a subsequent recovery period (68 +/- 12 ng/ml at 6 h). In four control fetuses and in the ewes, plasma IGF-I concentrations were not significantly different from control values (97 +/- 18 and 181 +/- 18 ng/ml, respectively). These data support the hypothesis that decreases in fetal oxygen availability may decrease fetal growth by decreasing IGF-I production and availability.

scholarly journals Chronic pulsatile infusion of growth hormone to growth-restricted fetal sheep increases circulating fetal insulin-like growth factor-I levels but not fetal growth

2003 ◽  
Vol 177 (1) ◽  
pp. 83-92 ◽  
Author(s):  
MK Bauer ◽  
BB Breier ◽  
FH Bloomfield ◽  
EC Jensen ◽  
PD Gluckman ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Blood Glucose ◽  
Growth Factor ◽  
Fetal Growth ◽  
Fetal Blood ◽  
Gh Treatment ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Igf I ◽  
Blood Glucose Concentrations

Intra-uterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity. Postnatally, growth hormone (GH) increases growth, increases circulating insulin-like growth factor (IGF)-I levels, and alters metabolism. Our aim was to determine if GH infusion to IUGR fetal sheep would alter fetal growth and metabolism, and thus provide a potential intra-uterine treatment for the IUGR fetus. We studied three groups of fetuses: control, IUGR+ vehicle and IUGR+GH (n=5 all groups). IUGR was induced by repeated embolisation of the placental vascular bed between 110 and 116 days of gestation (term=145 days). GH (3.5 mg/kg/day) or vehicle was infused in a pulsatile manner from 117 to 127 days of gestation. Embolisation reduced fetal growth rate by 25% (P<0.01) and reduced the weight of the fetal liver (20%), kidney (23%) and thymus (31%; all P<0.05). GH treatment further reduced the weight of the fetal kidneys (32%) and small intestine (35%; both P<0.04), but restored the relative weight of the fetal thymus and liver (P<0.05). Embolisation decreased fetal plasma IGF-I concentrations (48%, P<0.001) and increased IGF binding protein 1 (IGFBP-1) concentrations (737%, P<0.002). GH treatment restored fetal plasma IGF-I concentrations to control levels, while levels in IUGR+vehicle fetuses stayed low (P<0.05 vs control). IGFBP-1 and IGFBP-2 concentrations were about sevenfold lower in amniotic fluid than in fetal plasma, but amniotic and plasma concentrations were closely correlated (r=0.75, P<0.0001 and r=0.55 P<0.0001 respectively). Embolisation transiently decreased fetal blood oxygen content (40%, P<0.002), and increased blood lactate concentrations (213%, P<0.04). Both returned to pre-embolisation levels after embolisation stopped, but blood glucose concentrations declined steadily in IUGR+vehicle fetuses. GH treatment maintained fetal blood glucose concentrations at control levels. Our study shows that GH infusion to the IUGR fetal sheep restores fetal IGF-I levels but does not improve fetal growth, and further reduces the fetal kidney and intestine weights. Thus, fetal GH therapy does not seem a promising treatment stratagem for the IUGR fetus.

The effects of ovine placental lactogen infusion on metabolites, insulin-like growth factors and binding proteins in the fetal sheep

1995 ◽  
Vol 144 (2) ◽  
pp. 333-338 ◽  
Author(s):  
M H Oliver ◽  
J E Harding ◽  
B H Breier ◽  
P C Evans ◽  
B W Gallaher ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Binding Proteins ◽  
Amino Nitrogen ◽  
Late Gestation ◽  
Placental Lactogen ◽  
Fetal Blood ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Igf I ◽  
Igfbp 3

Abstract It has been suggested, but not shown, that in the fetus placental lactogen (PL) may affect the regulation of the IGFs and fetal metabolism. To examine the effects of PL on the circulating concentrations of the IGFs, IGF-binding proteins (IGFBPs), glucose, free fatty acids (FFAs) and amino nitrogen (AN), we infused late gestation sheep fetuses with recombinant ovine PL (roPL). Five chronically-catheterised sheep fetuses were infused intravenously with three 24 h infusions of saline, roPL (100 μg bolus then 500 μg over 24 h) and then saline again. Fetal roPL infusion increased plasma oPL from 0·4 ± 0·1 to 3·3 ± 0·5 nm (mean ± s.e.m.; P<0·05; factorial analysis of variance and Scheffé's test). Fetal plasma IGF-I, IGF-II, insulin, FFAs and blood glucose were unaffected by the roPL infusion. Fetal plasma IGFBP-3, as measured by Western ligand blotting, decreased by 30% during fetal roPL infusion while other fetal plasma IGFBPs were unaffected. Fetal roPL infusion decreased fetal blood AN from 7·3 ± 0·5 to 6·6 ± 0·2 mm (P<0·05). Maternal plasma IGF-I, IGF-II, IGFBPs, insulin, FFAs, blood glucose and AN were unaffected by the fetal roPL infusion. Saline infusion had no effect on any parameter. The data suggest that PL is not a significant determinant of plasma IGFs in the late gestation sheep fetus although there may be an indirect effect via alterations in levels of IGFBP-3. The effect of fetal roPL infusion on fetal blood AN concentrations may suggest some role for PL in the regulation of fetal amino acid metabolism. Journal of Endocrinology (1995) 144, 333–338

Effects of acute hypoxemia on insulin-like growth factors and their binding proteins in fetal sheep

1992 ◽  
Vol 263 (6) ◽  
pp. E1151-E1156 ◽  
Author(s):  
H. S. Iwamoto ◽  
M. A. Murray ◽  
S. D. Chernausek
Keyword(s):  
Fetal Growth ◽  
Recovery Period ◽  
Fetal Blood ◽  
Fetal Sheep ◽  
Oxyhemoglobin Saturation ◽  
Subsequent Recovery ◽  
Factor I ◽  
Igf I ◽  
Vascular Catheters ◽  
Insulin Like Growth Factors

It has been proposed that insulin-like growth factor I (IGF-I) regulates fetal growth and differentiation. Plasma IGF-I concentrations correlate positively with fetal nutrient availability and newborn birth weights. To explore the hypothesis that hypoxemia decreases fetal growth by decreasing fetal IGF-I availability, we instrumented 14 fetal sheep with vascular catheters. At least 4 days after surgery, 10 fetuses were made acutely hypoxemic by infusing nitrogen into the maternal trachea for 3 h. Fetal blood oxyhemoglobin saturation decreased from 53 +/- 6 (SD) to 31 +/- 9%. Concomitantly, plasma IGF-I concentrations decreased from 91 +/- 11 to 67 +/- 10 ng/ml and IGF-I binding protein-1 concentration increased significantly, as assessed by ligand and Western blot analysis. Fetal IGF-I concentrations remained below control values throughout a subsequent recovery period (68 +/- 12 ng/ml at 6 h). In four control fetuses and in the ewes, plasma IGF-I concentrations were not significantly different from control values (97 +/- 18 and 181 +/- 18 ng/ml, respectively). These data support the hypothesis that decreases in fetal oxygen availability may decrease fetal growth by decreasing IGF-I production and availability.

scholarly journals The effect of intermittent umbilical cord occlusion on insulin-like growth factors and their binding proteins in preterm and near-term ovine fetuses

2000 ◽  
Vol 166 (3) ◽  
pp. 565-577 ◽  
Author(s):  
LR Green ◽  
Y Kawagoe ◽  
DJ Hill ◽  
BS Richardson ◽  
VK Han
Keyword(s):  
Skeletal Muscle ◽  
Growth Factors ◽  
Umbilical Cord ◽  
Fetal Growth ◽  
Binding Proteins ◽  
Negative Impact ◽  
Mrna Levels ◽  
Igf I ◽  
Near Term ◽  
Insulin Like Growth Factors

Intermittent umbilical cord compression with resultant fetal hypoxia can have a negative impact on fetal growth and development. Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are the most important regulators of fetal growth. In preterm (107-108 days of gestation) and near-term (128-131 days of gestation) ovine fetuses, we have determined the effect of intermittent umbilical cord occlusion (UCO) over a period of 4 days on the profile and expression of IGFs and IGFBPs. In experimental group animals (preterm n=7; near term n=7) UCOs were carried out by complete inflation of an occluder cuff (duration 90 s) every 30 min for 3-5 h each day, while control fetuses (preterm n=7; near term n=7) received no UCOs. Ewes were euthanized at the end of day 4, and fetal heart, lung, kidney, liver, skeletal muscle and placenta were collected. During UCOs, PO(2! ) fell (by approximately 13 mmHg), pH fell (by approximately 0.05) and PCO(2) increased (by approximately 7 mmHg), and changed to a similar extent in both preterm and near-term groups. In both preterm and near-term groups, there was no difference in fetal body or organ weight between UCO and control fetuses. No significant changes were observed in plasma IGF-I and -II concentrations or IGFBP-1, -2, -3 or -4 levels throughout the 4-day study at either gestational age. In the preterm group UCO fetuses, IGF-II mRNA (1.2-6.0 kb) levels were lower in fetal lung (33%, P<0.05), heart (54%, P<0.01) and skeletal muscle (29%, P<0.05), but there were no differences in IGF-I mRNA levels (7.3 kb); IGFBP-2 mRNA (1.5 kb) levels were lower in the right lobe of the liver (42%, P<0.05) and kidney (22%, P<0.01), but hig! her in the heart (72%, P<0.01), while IGFBP-4 (2.4 kb) levels were lower in skeletal muscle (21%, P<0.01). In the near-term group UCO fetuses, IGFBP-2 mRNA levels were greater in the placenta (39%, P<0.05). Thus, intermittent UCO as studied has a greater effect on the expression of genes encoding certain peptides of the fetal IGF system in selected tissues in preterm fetuses than that in near-term fetuses. Altered IGFBP-2 mRNA levels with reduced IGF-II mRNA levels in selected tissues may mediate changes in growth and/or differentiation that might become apparent if the length of the UCO study were extended.

Circulating insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs) and tissue mRNA levels of IGFBP-2 and IGFBP-4 in the ovine fetus

1995 ◽  
Vol 145 (3) ◽  
pp. 545-557 ◽  
Author(s):  
J M Carr ◽  
J A Owens ◽  
P A Grant ◽  
P E Walton ◽  
P C Owens ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Mrna Level ◽  
Common Factor ◽  
Late Gestation ◽  
Mrna Levels ◽  
Igf Binding Proteins ◽  
Fetal Sheep ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

Abstract The IGF-binding proteins (IGFBPs) are a family of at least six structurally related proteins, which bind the IGFs and modulate their actions, including the regulation of preand postnatal growth. In this study we have examined the relationship between circulating and tissue mRNA levels of IGFBPs and related this to circulating IGFs in the fetal sheep over the gestational period when rapid growth and development occurs. Circulating IGFBP-2, as measured by Western ligand blot (WLB), increases between early and mid gestation, remains high, then declines throughout late gestation (P=0·0002). Circulating IGFBP-3 increases throughout gestation, as measured by WLB or RIA (P=0·04 and P=0·0001 respectively), as does circulating IGFBP-4 (P=0·004). These ontogenic changes in circulating IGFBPs-2 and -4 are paralleled by changes in liver mRNA for these proteins and, for IGFBP-2, by those in kidney IGFBP-2 mRNA also. This suggests that liver and kidney may be the primary contributors to circulating IGFBP-2 and the liver to circulating IGFBP-4. IGFBP-2 mRNA is present in the heart and lung in early gestation but barely detectable in these tissues after approximately 60 days gestation. IGFBP-4 mRNA is also present in the heart in early but not late gestation, but is abundant in the lung throughout gestation. These results demonstrate tissue specific and developmental regulation of IGFBPs-2 and -4 at the mRNA level. To assess any role the circulating IGFs may play in mediating these changes in IGFBPs, or vice versa, both plasma IGF-I and IGF-II were measured by RIA. Circulating IGF-I increases as gestation progresses (P=0·0001), while circulating IGF-II increases between early and mid gestation, remains high (P=0·01), then declines. Circulating IGF-I is positively correlated with fetal weight (r=0·66, P=0·03), circulating IGFBP-3 (r=0·54, P=0·01) and IGFBP-4 (r=0·52, P=0·01). Circulating IGF-II positively correlates with circulating IGFBP-2 (r=0·48, P=0·02) throughout gestation and at 1 day postnatally. These relationships are consistent with circulating IGF-I influencing IGFBPs-3 and -4, and similarly, IGF-II determining IGFBP-2, or vice versa. Alternatively, these correlations may reflect coordinate regulation of IGF and IGFBP by a common factor. Journal of Endocrinology (1995) 145, 545–557

scholarly journals Interstitial IGF-I in exercising skeletal muscle in women

2007 ◽  
Vol 157 (4) ◽  
pp. 427-435 ◽  
Author(s):  
U Berg ◽  
T Gustafsson ◽  
C J Sundberg ◽  
L Kaijser ◽  
C Carlsson-Skwirut ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Forms ◽  
Igf I ◽  
Igf Binding ◽  
Muscle Compartment ◽  
Level Of Significance ◽  
Igf Binding Protein ◽  
Design And Methods ◽  
Local Release ◽  
Igfbp 3

Objective: To study interstitial IGF-I concentrations in resting and exercising skeletal muscle in relation to the circulating components of the IGF–IGF binding protein (IGFBP) system. Design and methods: Seven women performed endurance exercise with 1 leg (Ex-leg) for 1 h. The resting leg (Rest-leg) served as a control. IGF-I was determined in microdialysate (MD) and was compared with veno-arterial (v-a) concentrations of circulating IGF–IGFBP components. Results: Median (range) basal MD-IGF-I was 0.87 (0.4–1.5) μg/l or 0.4 (0.2)% of total-IGF-I (t-IGF-I) determined in arterial serum and in the same concentration range as free dissociable IGF-I (f-IGF-I). Rest-leg MD-IGF-I decreased, reaching significance after exercise. Ex-leg MD-IGF-I was unchanged during exercise and declined after exercise at the level of significance (P = 0.05). There was a release of f-IGF-I from the Ex-leg into the circulation at the end of and shortly after exercise. A small but significant increase in circulating IGFBP-1 was detected at the end of exercise and IGFBP-1 increased further after exercise. Although interleukin-6 (IL-6) has been associated with IGFBP-3 proteolysis, the circulating molecular forms of IGFBP-3 remained unchanged in spite of an IL-6 release from the muscle compartment. Conclusions: Circulating IGFBP-1 is related to interstitial IGF-I in resting muscle although the temporal relationship may not be simple. Further studies should explore the role of local release of IGF-I and its impact on IGF-I activity during contraction.

Intravenous infusion of insulin-like growth factor I in fetal sheep reduces hepatic IGF-I and IGF-II mRNAs

1996 ◽  
Vol 271 (6) ◽  
pp. R1632-R1637 ◽  
Author(s):  
K. L. Kind ◽  
J. A. Owens ◽  
F. Lok ◽  
J. S. Robinson ◽  
K. J. Quinn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Intravenous Infusion ◽  
Feedback Inhibition ◽  
Fetal Liver ◽  
Plasma Concentrations ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep ◽  
Igf I

Liver contains the highest concentrations of insulin-like growth factor (IGF) I mRNA in adult rats and sheep and is a major source of circulating IGF-I. In rats, inhibition of hepatic IGF-I production by exogenous IGF-I has been reported. In fetal sheep, skeletal muscle and liver are major sites of IGF-I synthesis and potential sources of circulating IGF-I. To determine whether feedback inhibition of IGF gene expression in fetal liver or muscle by IGF-I occurs, IGF-I and IGF-II mRNAs were measured in these tissues after intravenous infusion of recombinant human IGF-I into fetal sheep. Infusion of IGF-I (26 +/- 4 micrograms.h-1.kg-1; n = 6) or saline (n = 6) commenced on day 120 of pregnancy (term = 150 days) and continued for 10 days. Plasma concentrations of IGF-I were threefold higher in infused fetuses at 130 days of gestation (P < 0.0003), whereas those of IGF-II were unchanged. IGF-I infusion reduced the relative abundance of IGF-I mRNA (P < 0.0002) and IGF-II mRNA (P < 0.01) in fetal liver by approximately 50% but did not alter IGF-I or IGF-II mRNA in skeletal muscle. These results indicate that IGF-I inhibits the expression of both IGF-I and IGF-II genes in fetal liver and that IGF gene expression in fetal liver and muscle is differentially regulated by IGF-I.

scholarly journals Isolation and validation of human prepubertal skeletal muscle cells: maturation and metabolic effects of IGF-I, IGFBP-3 and TNFα

2005 ◽  
Vol 568 (1) ◽  
pp. 229-242 ◽  
Author(s):  
Malcolm Grohmann ◽  
Emily Foulstone ◽  
Gavin Welsh ◽  
Jeff Holly ◽  
Julian Shield ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Metabolic Effects ◽  
Igf I ◽  
Igfbp 3
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