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The impact of placental SLC2A3 (GLUT-3) RNA interference on fetal growth and physiology at mid-gestation in sheep

dc.contributor.authorLynch, Cameron S., author
dc.contributor.authorAnthony, Russell V., advisor
dc.contributor.authorTesfaye, Dawit, committee member
dc.contributor.authorEngle, Terry, committee member
dc.description.abstractGlucose is the primary energy substrate for fetal oxidative processes and growth. In order for glucose to be transported from maternal to fetal circulation in the ruminant placenta, it must be sequentially transported by SLC2A1 (GLUT-1) on the maternal-fetal syncytial layer, then by SLC2A3 (GLUT-3) on the apical trophoblast membrane, and again by SLC2A1 on the basolateral trophoblast membrane. SLC2A1 is the most abundant placental facilitative glucose transporter, and as such, is believed to be the primary glucose transporter in human and sheep placenta. However, SLC2A3 exhibits a five-fold greater affinity and transport capacity for glucose. As such, in addition to its location on the apical trophoblast membrane, any deficiency in SLC2A3 could impact trophoblast glucose uptake and placental transfer of glucose to the fetus, thus potentially altering placental development and setting the stage for fetal hypoglycemia and intrauterine growth restriction (IUGR). It was our objective to use placenta-specific RNA interference (RNAi) to diminish SLC2A3, and determine the impact at mid- gestation (75 dGA) in sheep. The resulting pregnancies underwent a terminal surgery at 75 dGA. SLC2A3 RNAi resulted in a 37% reduction (p ≤ 0.05) in placental SLC2A3 concentration. SLC2A3-deficiency resulted in decreased fetal growth as evident by reduced fetal weight (p ≤ 0.10), head circumference (p ≤ 0.05), femur length (p ≤ 0.05), and tibia length (p ≤ 0.05). While there were no significant reductions in maternal glucose or insulin concentrations, the SLC2A3 RNAi pregnancies had decreased umbilical vein (p ≤ 0.05) and umbilical artery (p ≤ 0.05) glucose concentrations, as well as reduced umbilical artery insulin (p ≤ 0.10). Additionally, apparent attempts at compensation for SLC2A3-deficiency, by increasing SLC2A1, CSH, and IGF-2, were unable to prevent fetal hypoglycemia and the impacts on fetal development. Placental SLC2A1 concentration were increased (p ≤ 0.10), however this increase in expression was unable to prevent fetal hypoglycemia. The significant increase in umbilical vein CSH concentrations (p ≤ 0.05) appeared to preserve fetal liver weight and circulating umbilical concentrations of IGF-1, both of which are commonly decreased in IUGR pregnancies. SLC2A3-deficiency also resulted in a significant increase in IGF-2 (p ≤ 0.05), IGF1R (p ≤ 0.05), and IGF2R (p ≤ 0.05) expression. This suggests an apparent attempt to increase placental growth via IGF-2 acting through IGF1R, while IGF2R, which primarily acts to sequester and degrade IGF-2, doesn't allow placental growth to be overstimulated. While it has been suggested that SLC2A3 is predominantly important in late gestation, our data indicate that SLC2A3 is important for normal fetal development and appears to be a rate limiting glucose transporter during the first-half of gestation. A deficiency in SLC2A3 impacts trophoblast glucose uptake and subsequently glucose transfer to the fetus, and appears to set the stage during early gestation for the development of IUGR.
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dc.publisherColorado State University. Libraries
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dc.titleThe impact of placental SLC2A3 (GLUT-3) RNA interference on fetal growth and physiology at mid-gestation in sheep
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