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Placenta , 28 Aug , 34 11 : DOI: Free to read. Transport of glucose from maternal blood across the placental trophoblastic tissue barrier is critical to sustain fetal growth.

The mechanism by which GLUTs are regulated in trophoblasts in response to ischemic hypoxia encountered with intra-uterine fetal growth restriction IUGR has not been suitably investigated.

Further studies are needed to elucidate whether increased GLUT3 expression in IUGR is a marker for defective villous maturation or an adaptive response of the trophoblast in response to chronic hypoxia. Altered placental glucose transport due to chronic hypoxia may play a critical role in the pathophysiological events causing fetal intrauterine growth restriction IUGR , a condition linked to increased newborn mortality and adult onset of chronic diseases such as diabetes and cancer [ 1 , 2 ].

Glucose, which is essential for oxidative metabolism in the growing placenta and fetus, is transferred from maternal blood by facilitated carrier-mediated diffusion via glucose transporters. There are 14 known isoforms of the membrane-spanning glucose transporter family the GLUTs , which are responsible for facilitated diffusion of glucose across the lipid bilayers of cell membranes [ 3 ].

GLUT1, the main isoform expressed in mammalian placental syncytium, is found in high concentrations throughout pregnancy [ 10 ]. Thus, GLUT3 is generally found in tissues that have a high rate of metabolic activity, such as neurons [ 11 ] and trophectoderm in pre-implantation embryos [ 12 ].

GLUT4 is distinguished as an insulin-sensitive isoform, which may mediate insulin-stimulated placental glucose uptake in early pregnancy [ 9 ]. The mechanism by which GLUTs are regulated in trophoblast in response to ischemic hypoxia has not been suitably investigated. Growth restricted pups due to Glut 3 placental heterozygosity demonstrated catch-up growth after birth, similar to the pattern of growth seen in human late-onset IUGR [ 12 ].

The majority of pregnancies affected by late-onset IUGR are cases most likely attributable to ischemic placental disease that leads to disturbances in utero-placental flow causing chronic placental hypoxia [ 14 , 15 ]. In other in-vitro studies using BeWo, a trophoblast-derived choriocarcinoma cell line, reduction in oxygen tension led to dose-dependent increases in GLUT1 and GLUT3 expression and to increased transepithelial glucose transport [ 20 , 21 ].

Increased placental transport of glucose in hypoxic conditions would potentially increase the concentration of glucose as an alternate metabolic fuel to both the placenta and fetus, in which gluconeogenesis is limited [ 26 ]. However in the human, the fetus affected by IUGR demonstrates hypoglycemia, the magnitude of which is correlated to the severity of growth restriction [ 27 ] and magnitude of decreased blood flow [ 28 ]. It is thus widely believed that in conditions of fetal hypoxia leading to IUGR, it is an excess consumption of glucose by the placenta that is responsible for a decreased rate of transplacental transport to the fetus [ 29 , 30 ].

Although late-term IUGR is thought to share the same placental etiology as preeclampsia, i. We hypothesized that stimulation of placental glucose transporter expression is an adaptive response to decreased uteroplacental perfusion and prolonged exposure to hypoxia, which is associated with late-term IUGR.

IUGR was defined by newborn weight below or at the 10 th percentile for their gestational age and a demonstrated trajectory of fetal growth deceleration in utero, diagnosed by prenatal ultrasound [ 33 ]. Expression of hypoxia-related genes in the term placenta has been found to be dependent on the sampling site within the placental disk, with increased expression of VEGF and other transcripts occurring close to the lateral chorionic plate, the site of greatest hypo-perfusion [ 35 ].

We therefore separated our placental biopsies according to proximity to the chorionic plate as follows; using sterile technique, we cut a triangular segment of the placenta, with its convex base at the lateral edge of the placenta and its apex at the placental center near the cord insertion site. This triangular segment was then divided into 2 horizontal segments, with the basal plate on the bottom maternal side and the chorionic surface on the top fetal side.

Both the decidual layer along the basal plate as well as the chorionic surface and membranes were removed by sharp dissection and placental fragments were obtained at the middle of the initial placental depth, approximately 10 mm from the basal and chorionic plates.

First-strand cDNA was synthesized from 0. Placental tissues were homogenized and cell lysates were centrifuged for 15 minutes at 14,xg and supernatants were collected for immunoblot analysis. DNA methylation was quantified by pyrosequencing, as previously described [ 37 ]. Central full-thickness placental samples were embedded in paraffin blocks and mounted onto slides.

The slides were deparaffinized in xylene and rehydrated in a graded series of ethanol and treated with methanol and hydrogen peroxide, and then incubated with Proteinase K Dako, CA. Negative control consisted of absent primary antibody.

Louis, MO at room temperature for 1 hour. The sections were then examined under a fluorescence microscope at 40x magnification. Positive control testis shows immunoreaction for GLUT3 brown in the maturing secondary spermatocytes and sperm A2. B Sections of three different subjects showing normal term placenta B1-B3 vs. GLUT3 is localized to the cytotrophoblast layer and the syncytiotrophoblast layer to a lesser degree.

Arrows indicate immunoreactive syncytium, as determined by their morphology and location relative to the intervillous space. Triangles show underlying cytotrophoblast layer. D4 and D8: negative controls performed by omission of primary antibody and showed that cross-staining did not occur.

IUGR, fetal aspect E2 vs. IUGR, maternal aspect E3. Arrows indicate immunoreactive syncytium. Computations were carried out using StatView 5. Figure 1A shows target genes that were quantified by quantitative real-time PCR with sequence-specific oligonucleotides.

We therefore focused further study on GLUT3. Relative quantification of PCR products was based on the Ct value differences between target and the housekeeping gene using the comparative Ct method Eukaryotic 18s rRNA Applied Biosystems was used as an internal control.

Representative blots are shown. DNA methylation analysis of placental GLUT3 promoter regions in placental biopsies obtained from the maternal and fetal sides in women with normal pregnancy and pregnancy affected by IUGR. Genomic DNA was processed by pyrosequencing. Figure 4A shows a positive immunoreaction for GLUT3 in the maturing secondary spermatocytes adjacent to the lumen of the seminiferous tubule and sperm in our positive control.

Negative control slides treated with bovine serum instead of primary antibody were negative Fig. Figure 4B demonstrates immunohistochemical staining of slides obtained from three different control placentas top row, slides 1—3 adjacent to three different IUGR-affected placentas bottom row, slides 4—6.

GLUT3 positive immunoreactivity brown was seen in both the cytotrophoblast and syncytiotrophoblast cytotrophoblast with greater staining than syncytiotrophoblast , Fig. IUGR placentas were notable for increased matrix-type fibrinoid deposition [ 38 ] and variable expression of GLUT3, with some terminal and intermediate villi staining positive, and adjacent villi of the same size remaining unlabeled.

Placental sections reveal high expression of GLUT3 in extravillous trophoblasts embedded in fibrinoid matrix Fig. GLUT3 protein expression red was detected in both the cytotrophoblast and syncytiotrophoblast, again with variable expression from villi to villi. The variable presence of GLUT3 may serve as a marker for differential ischemic hypoxia in certain villi, not being present in others.

Variable expression of GLUT3 protein is likely attributable to several factors. First, placental lesions of IUGR are related to underperfusion due to varying pathologies such as poor uteroplacental blood flow due to maternal vascular disease, decreased elaboration of terminal villi owing to abnormal fetoplacental angiogenesis, and chronic villitis [ 39 — 41 ].

The extent of placental damage is related to impaired fetal growth as evolving placental injury leads to compromise of placental gas exchange, causing progressive fetal hypoxia [ 42 ]. With damage to the trophoblast, there is an increased local activation of the coagulation cascade in the inter-villous space causing excessive deposition of perivillous fibrin.

Indeed, the IUGR placentas we obtained in this study were notable for increased fibrinoid deposition. Fibrinoid embeds placental villi, causing impaired transplacental gas and nutrient exchange.

Interestingly, we observed multiple examples of increased GLUT3 in the trophoblast of villi adjacent to fibrinoid deposition by immunohistochemistry in both normal placenta and placenta affected by IUGR or preeclampsia. It is likely that increased expression of GLUT3, specifically on the maternal aspect of the placenta, is caused by accumulation of perivillous fibrinoid extending from the basal plate, where primary maternal vascular lesions limit perfusion to the intervillous space.

In this study, GLUT3 was expressed by the cytotrophoblast, and to a lesser degree, the syncytiotrophoblast. Syncytiotrophoblast GLUT3 expression is not surprising given that in placentas derived from mice, rats and sheep, GLUT3 expression is seen in maternal-facing syncytiotrophoblast cells STBs that form the labyrinthine region responsible for materno-fetal transfer of glucose. This is similar to the findings of multiple investigators who have observed GLUT3 expression exclusively in the CTBs of human placenta in early pregnancy [ 43 — 45 ].

CTBs contain stem cells, which differentiate to become non-proliferative multinucleated STBs with cell fusion. A hypothesis for the reduction of GLUT3 with advancing gestation is that with extensive differentiation to STBs, there is cessation of active division of CTB stem cells and therefore decreased metabolic activity; in other words, GLUT3, which is highly associated with tissues that have a high rate of metabolic activity such as dividing CTBs, is no longer required to the same extent in the differentiated STB [ 46 ].

In , Clarson et. Future studies will address the question of whether increased GLUT3 expression in term placentas associated with IUGR may signify an adaptive deceleration of placental development to accommodate and survive the ischemic-hypoxic environment. Observed increasing fetal hypoglycemia, the magnitude of which is correlated to the severity of IUGR [ 27 ] and magnitude of decreased blood flow [ 28 ], may suggest that this mechanism backfires.

Increased GLUT3 within late-term IUGR CTB could plausibly lead to a reversal of transplacental glucose flux resulting in transport from the fetus into the placental tissue, as has been described with maternal hypoglycemia [ 47 ].

More likely, increased GLUT3 within late-term IUGR CTB helps supply an excess consumption of glucose by the placenta itself, leading to a decreased rate of transplacental transport to the fetus [ 29 , 30 ]. This finding suggests that with utero-placental vascular insufficiency, rather than down-regulating GLUT3 expression as seen with normal term placenta, there is continued CTB expression of GLUT3, as found under the low-oxygen conditions of the first trimester.

Further studies are needed to elucidate whether increased GLUT3 expression in IUGR is a marker for stem cells with a proliferative capacity resulting in defective villous maturation or an adaptive re-setting of the epithelial cell in response to various stimuli. We warmly thank Jeffrey A. Gornbeinfor his biostatistical assistance and Sanjali Kumar for her technical assistance.

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Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Read article at publisher's site DOI : Chassen S , Jansson T. Cited by 1 article PMID: Review Free to read. J Endocrinol , 3 , 16 Apr PLoS One , 13 3 :e, 28 Mar Biol Reprod , 98 5 , 01 May To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

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Asthma increases worldwide without any definite reason and patient numbers double every 10 years. Drugs used for asthma therapy relax the muscles and reduce inflammation, but none of them inhibited airway wall remodeling in clinical studies. Airway wall remodeling can either be induced through pro-inflammatory cytokines released by immune cells, or direct binding of IgE to smooth muscle cells, or non-immunological stimuli. Increasing evidence suggests that airway wall remodeling is initiated early in life by epigenetic events that lead to cell type specific pathologies, and modulate the interaction between epithelial and sub-epithelial cells. Animal models are only available for remodeling in allergic asthma, but none for non-allergic asthma. In human asthma, the mechanisms leading to airway wall remodeling are not well understood.

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