Abstract
Previous work in our laboratory demonstrated that over-expression of human insulin-like growth factor -1 (hIGF-1) in the placenta corrects fetal weight deficits in mouse, rat, and rabbit models of intrauterine growth restriction without changes in placental weight. The underlying mechanisms of this effect have not been elucidated. To investigate the effect of intra-placental IGF-1 over-expression on placental function we examined glucose transporter expression and localization in both a mouse model of IUGR and a model of human trophoblast, the BeWo Choriocarcinoma cell line.MethodsAt gestational day 18, animals were divided into four groups; sham-operated controls, uterine artery branch ligation (UABL), UABL+Ad-hIGF-1 (108 PFU), UABL+Ad-LacZ (108 PFU). At gestational day 20, pups and placentas were harvested by C-section. For human studies, BeWo choriocarcinoma cells were grown in F12 complete medium +10%FBS. Cells were incubated in serum-free control media ±Ad-IGF-1 or Ad-LacZ for 48 hours. MOIs of 10∶1 and 100∶1 were utilized. The RNA, protein expression and localization of glucose transporters GLUT1, 3, 8, and 9 were analyzed by RT-PCR, Western blot and immunohistochemistry.ResultsIn both the mouse placenta and BeWo, GLUT1 regulation was linked to altered protein localization. GLUT3, localized to the mouse fetal endothelial cells, was reduced in placental insufficiency but maintained with Ad-I GF-1 treatment. Interestingly, GLUT8 expression was reduced in the UABL placenta but up-regulated following Ad-IGF-1 in both mouse and human systems. GLUT9 expression in the mouse was increased by Ad-IGF-1 but this was not reflected in the BeWo, where Ad-IGF-1 caused moderate membrane relocalization.ConclusionEnhanced GLUT isoform transporter expression and relocalization to the membrane may be an important mechanism in Ad-hIGF-1mediated correction of placental insufficiency.
Highlights
Fetal growth is reliant upon the proper growth and function of the placenta
To further validate the translational relevance of these findings, we investigated the effects of adenoviral IGF1 mediated changes in glucose transporters in vitro in human trophoblasts using the BeWo Choriocarcinoma model
Mouse placental GLUT1 mRNA expression was reduced by 30% (p,0.01, n.5) in the uterine artery branch ligation (UABL) group compared to sham but remained at this reduced level following Ad-human insulin-like growth factor -1 (hIGF-1) treatment
Summary
Fetal growth is reliant upon the proper growth and function of the placenta. In pathological pregnancies altered placental function can lead to inappropriate fetal growth, whether growth restricted or macrosomic, the offspring face increased risk of health problems in both childhood and later life.Appropriate placental function includes the transport of nutrients from the maternal circulation and both placental and fetal growth is dependent upon transfer of amino acids, fatty acids and glucose. Fetal growth is reliant upon the proper growth and function of the placenta. In pathological pregnancies altered placental function can lead to inappropriate fetal growth, whether growth restricted or macrosomic, the offspring face increased risk of health problems in both childhood and later life. Appropriate placental function includes the transport of nutrients from the maternal circulation and both placental and fetal growth is dependent upon transfer of amino acids, fatty acids and glucose. Efficient placental (maternal to fetal) transfer of glucose, the primary substrate for fetal oxidative metabolism, is crucial to sustain the normal development and survival of the fetus in utero because its own glucose production is minimal [1]. GLUT 1, 3, 8, 9a and 9b expression has been demonstrated in the mammalian placenta [3,4,5,6]
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