Molecular Biology Division, National Institute of Nutrition, Indian Council of Medical Research, Hyderabad, 500,007, India.
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
Mol Cell Biochem. 2019 Jan;451(1-2):91-106. doi: 10.1007/s11010-018-3396-7. Epub 2018 Jul 12.
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 (25 mM) 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 11 mM glucose. Cobalt chloride (CoCl)-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 HIF1α expression than by hypoxia alone. Cytochalasin B (cyt-B) inhibited the glucose uptake both in the presence of 11 mM and 25 mM glucose. Insulin (1 ng/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.
在早期妊娠中，缺氧条件通过最佳的葡萄糖代谢和转运体活性来维持。葡萄糖是胎盘形成所需的易于获得的能量营养物质。然而，关于葡萄糖摄取及其在妊娠早期胎盘形成过程中的转运体的数据有限。为此，本研究使用早期妊娠来源的滋养层细胞 HTR8/SVneo 和妊娠早期人胎盘组织外植体，研究了葡萄糖和葡萄糖转运体（GLUTs）在缺氧条件下对滋养层迁移和胎盘血管生成过程的影响。与存在 11mM 葡萄糖相比，外源性添加葡萄糖（25mM）可显著增加 HTR8/SVneo 细胞的管形成（体外血管生成），同时激活 AKT-PI3K 通路并增加血管细胞黏附分子 1（VCAM1）的表达。氯化钴（CoCl）诱导的缺氧也显著增加了 HTR8/SVneo 细胞的葡萄糖摄取和 GLUT1 表达，同时促进了管形成和迁移。在缺氧条件下，与单独缺氧相比，添加葡萄糖进一步刺激了 HIF1α 的表达。细胞松弛素 B（cyt-B）抑制了 11mM 和 25mM 葡萄糖存在时的葡萄糖摄取。胰岛素（1ng/ml）刺激 GLUT1 表达、管形成，并上调 HTR8/SVneo 细胞中 VEGFR2 的表达。胰岛素和葡萄糖刺激的管形成被 cyt-B 抑制，但对缺氧诱导的管形成没有影响。GLUT1 沉默抑制了葡萄糖和胰岛素刺激的管形成以及葡萄糖摄取。然而，GLUT1 敲低细胞中的脂肪酸刺激的管形成不受影响。所有这些数据表明，妊娠早期滋养层细胞 HTR8/SVneo 的葡萄糖摄取、葡萄糖刺激的管形成和胰岛素刺激的葡萄糖摄取部分通过 GLUT1 介导。
