Insulin-dependent, glucose transporter 1 mediated glucose uptake and tube formation in the human placental first trimester trophoblast cells

During early gestation, hypoxic condition is critically maintained by optimal glucose metabolism and transporter activities. Glucose is readily available energy nutrient required for placentation. However, limited data are available on glucose uptake and its transporters during first trimester placentation processes. To this end, effects of glucose and the roles of glucose transporters (GLUTs) were investigated during hypoxia on trophoblast migration and placental angiogenesis processes using early gestation-derived trophoblast cells, HTR8/SVneo, and first trimester human placental explant tissues. Exogenously added glucose (25mM) significantly increased tube formation (in vitro angiogenesis) in HTR8/SVneo cells with concomitant activation of AKT-PI3K pathway and increased expression of vascular cell adhesion molecule 1 (VCAM1) compared with those in the presence of 11mM glucose. Cobalt chloride (CoCl2)-induced hypoxia also significantly increased glucose uptake and GLUT1 expression along with tube formation and migration of HTR8/SVneo cells. During hypoxia, addition of glucose further stimulated HIF1 expression than by hypoxia alone. Cytochalasin B (cyt-B) inhibited the glucose uptake both in the presence of 11mM and 25mM glucose. Insulin (1ng/ml) stimulated GLUT1 expression and tube formation and up-regulated the expression of VEGFR2 in HTR8/SVneo cells. Insulin and glucose-stimulated tube formation was inhibited by cyt-B but had no effect on hypoxia-induced tube formation. Silencing of GLUT1 inhibited the glucose and insulin-stimulated tube formation as well as glucose uptake. However, fatty acid-stimulated tube formation was not affected in GLUT1 knockdown cells. All these data suggest that glucose uptake, glucose-stimulated tube formation, and insulin-stimulated glucose uptake of the first trimester trophoblast cells, HTR8/SVneo, are mediated in part via GLUT1.