Intrauterine Growth Restriction Placentas Research Articles

Histopathological analysis of the placental lesions in pregnancies complicated with IUGR and stillbirths in comparison with noncomplicated pregnancies

Placental factors and hypoxemia are the keys to intrauterine growth restriction (IUGR) and stillbirth. The aim of the study is to analyze histological changes in placentas of IUGR fetuses in pregnancies with no apparent etiologic factor and unexplained intrauterine fetal deaths. A total of 110 placentas were collected; 26 placentas of IUGR fetuses with no apparent cause, 58 placentas from unexplained intrauterine deaths over 20 weeks of gestation, and 26 placentas from uncomplicated pregnancies who delivered a healthy live baby. Microscopic examinations of placentas were performed for histopathological analyzes. Gestational age at delivery was 33.67±4.37 weeks, 29.15±8.36 weeks, and 39.0±1.52 weeks in women in group I, group II and group III, respectively (p<0.01). Infarction and intervillous thrombosis are significantly more frequent in placentas of Group I and group II. Chronic villitis occurred in 69%, 63% and 30% of group I, group II, and group III, respectively. Placental intravascular thrombi (Group I, 31% and group II, 26%), perivillous fibrin deposition and fibrinoid necrosis (65% in Group I and 53% in group II), infarction, intervillous thrombosis, chronic villitis, hemorrhagic endovasculitis, placental intravascular thrombi, perivillous fibrin deposition, fibrinoid necrosis, erythroblastosis and villous edema were found in the study group. The results reported here indicate that a relationship exists between morphological changes in the placentas of IUGR and intrauterine fetal deaths.

The expression of Akt and ERK1/2 proteins decreased in dexamethasone-induced intrauterine growth restricted rat placental development

The placenta is a complicated tissue that lies between maternal and fetal compartments. Although the architecture of the human and rodent placentas differ a little in their details, their overall structures and the molecular mechanisms of placental developments are thought to be very similar. In rats, fetal-placental exposure to maternally administered glucocorticoids decreases birth weight and placental weight. The mechanism underlying the placental growth inhibitory effects of glucocorticoids have not been elucidated. Moreover it is still not determined that how Akt and ERK1/2 proteins related proliferation and apoptosis mechanisms are influenced by dexamethasone-induced IUGR (Intrauterine Growth Restriction) placentas. The aim of this study was to investigate the expression levels and spatio-temporal immunolocalizations of Akt, p-Akt, ERK1/2 and p-ERK1/2 proteins in normal and dexamethasone treated placental development in pregnant Wistar rats. Pregnant rats were subcutaneously injected with 100 μg/kg dexamethasone 21-acetate in 0.1 ml 10% ethanol on day 10 and 12 of gestation. Afterwards injection was continued as 200 μg/kg until they were killed on day 12 (injection started on day 10), 14, 16, 18 and 20 (injections started on day 12) of pregnancy. Placental and embryonal tissues were collected for immunohistochemistry and Western blot analysis. We found that maternal dexamethasone treatment led to a decrease in ERK1/2 and Akt activation during rat placental development. The decrease in Akt and ERK1/2 activations may result with cell survival inhibition or apoptosis stimulation. Hence, dexamethasone induced placental and embryonal developmental abnormalities could be associated with reduction of Akt and ERK1/2 activation.

707: Mechanisms of telomere shortening in placentas from pregnancies complicated with intrauterine growth restriction

Intrauterine Growth Restriction (IUGR) correlates with placental telomere shortening and senescence. Telomerase is an enzyme complex that elongates telomeres. Telomerase RNA component (TERC) gene serves as the RNA template for the addition of telomeric repeats. Telomerase reverse transctiptase (TERT) is the catalytic component of telomerase. We studies mechanisms of telomere shortening in IUGR placentas. We estimated the copy number of the TERC gene using FISH and the expression of TERT mRNA using RT-PCR, in placental biopsies from six pregnancies complicated with IUGR and from six gestational age matched controls. Lower TERC gene copy number was observed in IUGR trophoblasts (p<0.05). TERT mRNA was found to be diminished in IUGR placentas compared to control samples (mean fold of 0.5±0.2 and 0.96±0.1 respectively, p=0.0005). These results support and explain the observations of telomere shortening and decreased telomerase activity in IUGR placentas. We suggest that these findings may play a role in the pathophysiology of IUGR, perhaps by promoting senescence in trophoblasts of IUGR placentas.

Intervillous circulation in intra-uterine growth restriction. Correlation to fetal well being

Magnetic resonance imaging requested for a potentially serious indication, provided a unique opportunity to explore the intervillous circulation of placentas from pregnancies complicated by Intra Uterine Growth Restriction (IUGR) and to compare them to normal cases. This allowed an innovative characterization of in vivo utero-placental blood flow, correlating a compromised intervillous circulation in IUGR to the deterioration of fetal condition. MR imaging was requested to rule out suspected posterior placental adhesive disorders in 26 patients. Twelve patients had fetuses appropriate for gestational age, while in 14 patients fetuses were affected by severe IUGR. Multiphasic dynamic contrast-enhanced sagittal sequences were acquired and a quantitative analysis of signal intensity and enhancement kinetics was performed for both the entire placenta and for selected regions. Images disclosed a homogeneous perfusion overall the placenta in normal cases, while IUGR placentas displayed a slow intervillous blood flow, along with many patchy unperfused areas. Intermittent stops worsen the perfusion dynamics of the intervillous mostly in IUGR cases with an elevated ductus venosus pulsatility index. In conclusion, we proved that in IUGR placenta maternal placental blood flow is extremely compromised and that superimposed dynamic phenomena concur to worsen the intervillous circulation leading to an end-stage fetal decompensation.

Involvement of heparanase in vaginal and cesarean section deliveries

Background Heparanase is an endo-β-D-glucuronidase dominantly involved in cell invasion, tumor angiogenesis and metastasis. Recently, we demonstrated increased levels of heparanase, tissue factor pathway inhibitor (TFPI)-2 and vascular endothelial growth factor (VEGF)-A in early miscarriages (Nadir et al., Thromb Res, 2010). Herein, we investigated the role of heparanase in third trimester placentas, in correlation to tissue factor (TF), TFPI, TFPI-2, and VEGF-A. Methods Twenty five third-trimester placenta samples (weeks 36-41) were studied applying real time RTPCR and immunostaining. Ten cases were placentas of elective cesarean sections, 8 cases were of normal vaginal deliveries and 7 samples were placentas of intra-uterine growth restriction (IUGR) fetuses. Skin and lung tissues of heparanase over-expressing mice and heparanase knock-out mice were subjected to immunostaining. Results Sections obtained from vaginal and IUGR placentas revealed 2 folds increased levels of heparanase, TFPI-2 and VEGF-A compared to placentas from elective cesarean sections in maternal decidua as well as in fetal placenta elements. Interestingly, abundance of TFPI staining in the intra-villous blood was observed in placentas of vaginal and IUGR deliveries. Heparanase effect on TFPI release to the blood was supported by immunostaining of heparanase over-expressing and heparanase knock-out mice tissues. Conclusions In regard to our previous data on early pregnancy losses, the present data strengthen the understanding that in placental vascular complications levels of heparanase, TFPI-2 and VEGF-A increase. In the process of delivery, heparanase may have a regulatory role on TFPI release to fetal circulation.

Telomeres are shorter in placental trophoblasts of pregnancies complicated with intrauterine growth restriction (IUGR)

ObjectiveTelomeres are nucleoprotein structures located at the termini of chromosomes, and protect them from fusion and degradation. Telomeres are progressively shortened with each mitotic cycle and by environmental factors. We hypothesized that antepartum stress can lead to accelerated telomere shortening in placental trophoblasts, and plays a role in intrauterine growth restriction (IUGR). MethodsPlacental biopsies were derived from 16 pregnancies complicated with IUGR and from 13 uncomplicated pregnancies. Fluorescence-in-situ protocol was used to determine telomere length. Immunohistochemistry for hTERT was performed to assess telomerase activity. Clinical and histopathological characteristics were collected to ensure that IUGR was secondary to placental insufficiency. Fluorescence-in-situ-hybridization was used to rule out aneuploidy as a reason for shortened telomeres. ResultsThe number and intensity of telomeres staining and telomerase activity were significantly lower in the IUGR placentas. No aneuploidy was detected for the chromosomes checked in the placental biopsies. ConclusionsTelomeres are shorter in trophoblasts of IUGR placentas.

Expression of heat shock protein 70 and endothelial nitric oxide synthase in placental tissue of preeclamptic and intrauterine growth-restricted pregnancies

Ischemia, hypoxia, and elevated vascular resistance disturb placental functions by increasing oxidative stress. Heat shock protein 70 (HSP70) is an oxidative stress marker. Endothelial nitric oxide synthase (eNOS) is a nitric oxide enzyme with a key role in pathologic and physiologic angiogenesis and vasculogenesis. This study was performed to investigate the role of oxidative stress in the pathogenesis of preeclampsia and intrauterine growth-restricted (IUGR) pregnancies by comparing the levels of HSP70 and eNOS in placentas from women with these diseases and those with healthy pregnancies. HSP70 and eNOS were examined using the streptavidin-biotin-peroxidase complex technique on formalin-fixed, paraffin-embedded sections from 135 placental villous tissues obtained from normal pregnancies ( n = 45) and pregnancies complicated with preeclampsia ( n = 45) and IUGR ( n = 45). The intensity of labeling in placental tissues with antibodies to HSP70 and eNOS was scored between 0 and 3, using a semiquantitative scale. HSP70 and eNOS levels were increased in the syncytiotrophoblasts, cytotrophoblasts, and extravillous trophoblast cells of preeclamptic and IUGR placentas ( P < 0.001), compared with normal pregnancies. However, their levels were increased only in the villous endothelial cells of IUGR placentas ( P < 0.001). Oxidative stress is thought to play an important role in the pathogenesis of preeclampsia and IUGR pregnancies.

DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia

Preeclampsia and intrauterine growth restriction (IUGR) are two of the most common adverse pregnancy outcomes, but their underlying causes are mostly unknown. Although multiple studies have investigated gene expression changes in these disorders, few studies have examined epigenetic changes. Analysis of the DNA methylation pattern associated with such pregnancies provides an alternative approach to identifying cellular changes involved in these disorders. We analyzed methylation of 1505 CpG sites associated with 807 genes in 26 placentas from early-onset preeclampsia (EOPET), late-onset preeclampsia, IUGR and control subjects using an Illumina GoldenGate Methylation panel. Thirty-four loci were hypomethylated (false discovery rate <10% and methylation difference >10%) in the early-onset preeclamptic placentas while no and only five differentially methylated loci were found in late-onset preeclamptic and IUGR placentas, respectively. Hypomethylation of 4 loci in EOPET was further confirmed by bisulfite pyrosequencing of 26 independent placental samples. The promoter of TIMP3 was confirmed to be significantly hypomethylated in EOPET placentas (P=0.00001). Our results suggest that gene-specific hypomethylation may be a common phenomenon in EOPET placentas, and that TIMP3 could serve as a potential prenatal diagnostic marker for EOPET.

Volumes and Numbers of Intervillous Pores and Villous Domains in Placentas Associated with Intrauterine Growth Restriction and/or Pre-eclampsia

The intrauterine environment has an important influence on placental development. In pre-eclampsia (PE) and intrauterine growth restriction (IUGR), early remodelling of spiral arteries has repercussions for uteroplacental blood flow. The IUGR placenta exhibits compromised growth of villous trees, a smaller intervillous space and a lower diffusive conductance. Here, we test whether or not term placentas associated with PE or IUGR also exhibit changes in structural quantities (notably, sizes and numbers of intervillous pores and villous domains) pertinent to uteroplacental haemodynamics. Paraffin wax sections were sampled at random locations and orientations and structural quantities obtained by combining design-based stereological estimates of total and star volumes with model-based estimates of pore hydraulic diameters. Total volumes of intervillous pores and villi were estimated by point counting, total villous surface by intersection counting and star volumes by measuring point-sampled intercept lengths. Other quantities were derived secondarily and group estimates compared by two-way analysis of variance. We found significant main effects of IUGR but no main or interaction effects involving PE. In IUGR, there were fewer intervillous pores and these had larger hydraulic diameters. IUGR also produced fewer villous domains but these were constant in star volume and villi had a constant mean diameter and volume fraction. We concluded that IUGR compromises placental development by producing intervillous pores and villous trees different in size and shape from those in control and PE pregnancies. Calculations suggest that Darcian conductances in the intervillous space improve in IUGR but, in reality, placental performance is compromised by other physiological and structural constraints including the known decline in diffusive conductances.

Intrauterine growth restriction and placental angiogenesis

BackgroundVascular endothelial growth factor (VEGF), basic-fibroblast growth factor (b-FGF), and endothelial nitric oxide synthase (eNOS) are factors that take part in placental angiogenesis. They are highly expressed during embryonic and fetal development, especially in the first trimester. In this study, we aimed to investigate the role of placental angiogenesis in the development of intrauterine growth restriction (IUGR) by comparing the levels of expression of VEGF-A, b-FGF, and eNOS in normal-term pregnancy and IUGR placentas.MethodsThe expression of VEGF-A, b-FGF, and eNOS was studied using the avidin-biotin-peroxidase method in placental tissues diagnosed as normal (n = 55) and IUGR (n = 55). Results were evaluated in a semi-quantitative manner.ResultsThe expression of all the markers was significantly higher (p < 0.001) in cytotrophoblasts, syncytiotrophoblasts, extravillous trophoblasts, vascular smooth muscle cells, chorionic villous stromal cells, and villous vascular endothelial cells of the IUGR placentas when compared with those collected from normal-term pregnancies.ConclusionIncreased expression of VEGF-A, b-FGF, and eNOS may be the result of inadequate uteroplacental perfusion, supporting the proposal that abnormal angiogenesis plays a role in the pathophysiology of IUGR.

VEGF in the Muscular Layer of Placental Blood Vessels: Immuno- Expression in Preeclampsia and Intrauterine Growth Restrictrion and its Association with the Antioxidant Status

The pathophysiology of preeclampsia (PE), a disorder occurring in 5% of all pregnancies, remains largely unknown, but early placental hypoxia and oxidative stress are known to be involved in the mechanism of the syndrome. Maternal plasma and placental tissue samples were collected from PE, intrauterine growth restriction (IUGR), and normotensive pregnant patients. The immunohistochemical expression of vascular endothelial growth factor (VEGF), malondialdehyde (MDA) production and the activity of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase GSH-Px) were determined in the placental tissue. F2-isoprostane concentration and the ferric reducing ability of plasma (FRAP) were determined in maternal plasma. We found that the PE and IUGR groups showed a higher expression of VEGF in the muscular layer of fetal chorionic vessels. In addition, increased plasma F2 isoprostane levels and a significant reduction of FRAP in the plasma of PE women, as well as a lower activity of SOD in PE placentas and a higher activity of GSH-Px in IUGR placentas were found. Additionally, lower PlGF and higher sFlt1 levels were observed in the maternal plasma of PE and IUGR than control. We concluded that in a hypoxic environment, the placenta expresses VEGF in the muscular layer of fetal vessels. The development of PE could be related to the increased expression of VEGF, with decreased placental SOD activity and a decrease of both plasma F2-isoprostane and FRAP levels. In turn, the development of IUGR could be related to the association of decreased plasma FRAP levels and increased placental GSH-Px activity.

Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction

Telomeres shorten and aggregate with cellular senescence and oxidative stress. Telomerase and its catalytic component human telomerase reverse-transcriptase regulate telomere length. The pathogenesis of preeclampsia and intrauterine growth restriction involves hypoxic stress. We aimed to assess telomere length in trophoblasts from pregnancies with those complications. Placental specimens from 4 groups of patients were studied: severe preeclampsia, intrauterine growth restriction, preeclampsia combined with intrauterine growth restriction, and uncomplicated (control). Telomere length and human telomerase reverse-transcriptase expression were assessed by using quantitative fluorescence-in-situ protocol and immunohistochemistry. Telomere length was significantly lower in preeclampsia, intrauterine growth restriction, and preeclampsia plus intrauterine growth restriction placentas. More aggregates were found in preeclampsia, but not in intrauterine growth restriction placentas. Human telomerase reverse-transcriptase was significantly higher in the controls compared with the other groups. Telomeres are shorter in placentas from preeclampsia and intrauterine growth restriction pregnancies. Increased telomere aggregate formation in preeclampsia but not in intrauterine growth restriction pregnancies, implies different placental stress-related mechanisms in preeclampsia with or without intrauterine growth restriction.

Microarray analysis of placental tissue in intrauterine growth restriction

Besides foetal or maternal disorders, placental dysfunction is a major cause of intrauterine growth restriction (IUGR). Although numerous macro- and histopathological changes have been described, little is known about the precise aetiology and the contribution of foetal/placental genes in this disorder. Placental tissues of 20 IUGR and control neonates were analysed by microarray technique. Four of the regulated genes with possible relevance in the pathogenesis of IUGR and its consequences were further studied in placentas of 27 IUGR and 35 control newborns. Elevated gene expression of leptin, corticotrophin-releasing hormone (CRH), and IGF-binding protein-1 (IGFBP-1) in IUGR placentas could be confirmed in the larger group by real-time PCR, whereas prolactin showed no significant difference. Accordingly, protein expression of leptin and IGFBP-1 depicted by Western blot was elevated in IUGR, prolactin was not different. Birthweight standard deviation score (SDS) correlated negatively to leptin, IGFBP-1, and CRH, whereas placental weight correlated only to IGFBP-1. Leptin correlated negatively to gestational age of IUGR patients and positively to placental score, a marker of severity of impaired foeto-placental circulation. As confirmed in a large group of IUGR and control samples, the up-regulated factors leptin, IGFBP-1, and CRH may serve as candidate genes for the prediction of subsequent metabolic consequences in IUGR newborns. These three factors may not only influence growth of the foetus, but might also interact with programming of its metabolic functions, which has to be determined in an ongoing study.

Decreased Placental Methylation at the H19/ IGF2 Imprinting Control Region is Associated with Normotensive Intrauterine Growth Restriction but not Preeclampsia

Many genes exhibiting genomic imprinting, parent-of-origin differences in gene expression, are involved in regulating placental and fetal growth. The goal of the present study was to assess whether abnormal regulation of imprinted genes is associated with intrauterine growth restriction (IUGR) and/or preeclampsia (PET). Methods Genomic DNA was extracted from at least two whole villi samples from control ( N = 22), IUGR ( N = 13), PET ( N = 17), and PET + IUGR ( N = 21) placentas. Methylation was assessed using the Illumina GoldenGate Methylation Cancer Panel I array and Pyrosequencing and MS-SNuPE assays. Results The 11p15.5 ICR1 (associated with H19 and IGF2) methylation showed considerable intra-placental variability. Nonetheless, average methylation at this site was significantly decreased in normotensive IUGR placentas ( p < 0.001), but not in any other group. Methylation at ICR2 (KvDMR1; associated with CDKN1C and other maternally expressed 11p15.5 genes) was not significantly altered in any group and no significant changes in expression levels were observed in the genes controlled by this region. There were no significant methylation changes observed in any candidate imprinted gene evaluated by the Illumina array. LINE-1 methylation, a marker of whole genome methylation, was also similar in all groups. Conclusions Reduced methylation of ICR1 is associated with normotensive IUGR but not IUGR associated with preeclampsia, suggesting a different etiology of IUGR in this group. A reduction in placental IGF2 could be an adaptive response to restrict fetal growth in the presence of abnormal placentation or a response to poor fetal growth itself.

Differences in gene expression dependent on sampling site in placental tissue of fetuses with intrauterine growth restriction

Objective The human placenta as part of the feto-placental unit may influence fetal endocrine systems and may therefore represent a very important link between intrauterine growth restriction (IUGR) and metabolic disorders in later life. We aimed to analyze the effect of sample origin on gene expression of placental factors potentially involved in fetal programming in IUGR versus appropriate for gestational age growth (AGA) to standardize sample collection procedure for a multicenter approach. Design Placental gene expression of insulin-like growth factor-binding protein (IGFBP)-1, prolactin, corticotropin releasing hormone (CRH) and leptin was measured and compared between proximal, intermediate and peripheral region of the placenta in 22 IUGR (proven by anomalous placental Doppler velocimetry) and 19 AGA neonates. Results Whereas no difference in gene expression was seen in the proximal portion, in the intermediate placental region mRNA expression of IGFBP-1 ( p = 0.01), prolactin ( p = 0.04), CRH ( p = 0.01) and leptin ( p = 0.04) was increased in IUGR samples compared to controls. At the placental periphery, gene expression of these placental transcripts showed a higher expression level in IUGR placentas without statistical significance, except for leptin ( p = 0.03). Conclusion Placental sampling site seems to be relevant for detecting differences in gene expression between IUGR and AGA neonates.

Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: Gestational diabetes mellitus, intrauterine growth restriction and preeclampsia

Background Common complications of pregnancy arise in part from dysfunctional placental development, and include gestational diabetes mellitus (GDM), intrauterine growth restriction (IUGR) and preeclampsia (PE). Peroxisome proliferator-activated receptors (PPARs), and their partner retinoid X receptor a (RXRα), mediate trophoblast differentiation and thus may offer insight into the pathophysiology of these diseases. Methods Human placentae were obtained from women at term with GDM and were compared to uncomplicated term placentae. Placentae from women who delivered preterm with IUGR, PE or co-existing PE and IUGR were compared to matched controls. Quantitative RT-PCR and Western blotting were used to examine mRNA and protein expression of PPARα, PPARδ, PPARγ and RXRα. DNA binding activity of PPAR isoforms were measured in nuclear protein extracts. Results GDM was associated with significantly lower placental PPARγ mRNA and protein, PPARα protein and RXRα protein expression, while PPAR DNA binding activity remained unchanged. Placentae from women with PE did not demonstrate any changes in mRNA or protein expression or PPAR DNA binding activity, while IUGR/PE placenta showed significant increases in PPARα protein, PPARγ mRNA and protein and RXRα mRNA and protein expression. Significantly elevated protein expression of PPARα and RXRα were associated with IUGR placentae. IUGR and IUGR/PE placentae had significantly higher PPARγ DNA binding activity compared to controls. Conclusions The data presented herein suggest that PPARs may be involved in the pathophysiology of GDM, PE and IUGR.

Villous Trophoblast Cell Turnover in Placentas From Preterm Pregnancy and Pregnancy Complicated by Intrauterine Growth Restriction (IUGR)

Disturbed trophoblast turnover, a key process in placental physiology, may lead to a number of pregnancy-associated pathologies. This study examines PCNA expression and describes and quantifies morphological changes during trophoblast turnover in preterm placentas and term placentas complicated by IUGR. The number ofCTF cells increased two-fold in preterm and IUGR placentas. A concurrent and slightly reduced proliferation rate of these cells was also found. The number of STF nuclei of terminal villi was lower by 21% in IUGR and by 18% in preterm placentas (P > 0.05). A statistically significant reduction of the number of syncytial knots by 50% as compared to the control placentas was observed. Correlations between PCNA-reactive CTF nuclei and syncytial knots, PCNA-reactive CTF nuclei and CCO activity, and CCO activity and syncytial knots were found. Moreover, a strong inverse relation was observed between syncytial knots and CTF cells, and CCO activity and CTF cells.

Cullins in Human Intra-Uterine Growth Restriction: Expressional and Epigenetic Alterations

Intra-uterine growth restriction (IUGR) is defined by a restriction of fetal growth during gestation. It is a prevalent significant public health problem that jeopardizes neonatal health but also that can have deleterious consequences later in adult life. Cullins constitute a family of seven proteins involved in cell scaffold and in selective proteolysis via the ubiquitin-proteasome system. Most Cullins are critical for early embryonic development and mutations in some Cullin genes have been identified in human syndromes including growth retardation. Our work hypothesis is that Cullins, particularly CUL4B and CUL7, are involved in placental diseases and especially in IUGR. Thus, expression of Cullins and their cofactors was analyzed in normal and pathological placentas. We show that they present a constant significant over-expression in IUGR placentas, whose extent is dependent on the position of the interrogated fragment along the cDNAs, suggesting the existence of different isoforms of the genes. Particularly, the CUL7 gene is up-regulated up to 10 times in IUGR and 15 times in preeclampsia associated with IUGR. The expression of cofactors of Cullins participating to functional complexes has also been evaluated and showed a similar significant increase in IUGR. Promoters of Cullin genes appeared to be under the control of the SP1 transcription factor. Finally, methylation levels of the CUL7 promoter in placental tissues are modulated according to the pathological conditions, with a significant hypomethylation in IUGR. These results concur to pinpoint the Cullin family as a new set of markers of IUGR.

Intrauterine growth restriction, human placental development and trophoblast cell death

Intrauterine growth restriction (IUGR) is a failure to achieve the growth potential of a fetus that is promised by the genetic constitution and environmental influences endogenous to the pregnancy. Optimal placental development and the ability of the placenta to compensate for stimulus-induced injury are central in promotion of normal fetal growth. In this review, we will overview placental development with a focus on how villous structure relates to function. We will also describe the differentiation and turnover of villous trophoblast while highlighting selected features of microscopic placental injury. Histopathological studies of the placenta in IUGR indicate that abnormalities of the maternal spiral arterioles, dysregulated villous vasculogenesis, and abundant fibrin deposition are characteristic of the injuries associated with this condition. We identify selected insults, including oxidative stress and complement activation, and key pathways that regulate apoptosis in villous trophoblast, including increased p53 activity, altered translation of AKT and mTOR proteins, and the stress response of the endoplasmic reticulum. We surmise that trophoblast dysregulation at a subcellular level and loss of functional mass of villous trophoblast via cell death pathways are key contributors to the suboptimal placental performance that yields IUGR. We predict that a better understanding of placental dysfunction in IUGR will lead to targeted therapeutic options for this important clinical condition.

The Role of the Placenta in Intrauterine Growth Restriction (IUGR)

Intrauterine growth restriction (IUGR) represents a reduction from the physiological growth rate. Fetal growth depends from the maternal supply of nutrients through the placenta into the umbilical circulation. Consequently, fetal growth restriction is associated with a reduced nutritional placental supply and this can result from a decrease in utero-placental blood flows as well as a reduced placental transport capacity. In IUGR, the placental supply of amino acids is significantly reduced independently from the severity of growth restriction and from the presence of hypoxia. Moreover, maternal-fetal gradients of glucose are increased in severe IUGR fetuses, i. e. those with alterations of umbilical blood flows, and reduced conversion ratios of long chain-polyunsaturated fatty acids (LC-PUFA) from their parent fatty acids have been demonstrated. Mouse and human models suggest that epigenetic regulation of fetal growth may also play a significant role, through placental imprinted genes. This review summarizes the current knowledge about placental role in intrauterine growth restriction.