Inhibition of Human Trophoblast Invasiveness by High Glucose Concentrations

• Published in: The journal of clinical endocrinology and metabolism Vol. 90; no. 8; pp. 4846 - 4851
• Main Authors: Belkacemi, Louiza, Lash, Gendie E., Macdonald-Goodfellow, Shannyn K., Caldwell, Jason D., Graham, Charles H.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-08-2005
• Subjects: Biological and medical sciences; Cell Line, Transformed; Cell Movement - drug effects; Cell Movement - physiology; Dose-Response Relationship, Drug; Endocrinopathies; Extracellular Matrix - metabolism; Female; Fundamental and applied biological sciences. Psychology; Glucose - pharmacology; Glucose Transporter Type 1; Glucose Transporter Type 3; Humans; Matrix Metalloproteinases - metabolism; Medical sciences; Monosaccharide Transport Proteins - metabolism; Nerve Tissue Proteins - metabolism; Plasminogen Activator Inhibitor 1 - metabolism; Receptors, Cell Surface - metabolism; Receptors, Urokinase Plasminogen Activator; Trophoblasts - cytology; Trophoblasts - drug effects; Trophoblasts - metabolism; Urokinase-Type Plasminogen Activator - metabolism; Vertebrates: endocrinology; Pregnancy; Human; Trophoblaste; Fetal membrane; Inhibitor; Glucose; Inhibition; Endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2004-2242

Context: Trophoblast invasion of the uterus is regulated by local microenvironmental factors.
Objective: Because certain conditions may affect uterine glucose levels during placentation, the aim of this study was to determine the effect of glucose concentration on trophoblast invasion.
Results: Compared with incubation in 0.2 and 2.5 mm glucose, a 24-h incubation in increasing glucose concentrations (5 and 10 mm) resulted in up to a 62% inhibition (P < 0.01) of the in vitro invasiveness of immortalized HTR-8/SVneo trophoblasts. This decreased invasiveness in 5 and 10 mm glucose was paralleled by inhibition of a plasminogen activator (PA) activity corresponding to active urokinase-type PA (uPA). Inhibition of pro-uPA binding to the uPA receptor decreased the invasiveness of cells incubated in 0.2 and 2.5 mm glucose to levels observed in cells incubated in higher glucose concentrations (P < 0.05). Gelatin zymography and Western blot analysis revealed that the levels of matrix metalloproteinase-2 and -9, PA inhibitor-1, and uPA receptor were unaffected by glucose. Glucose transporter-1 levels were 26 and 34% higher in cells cultured in 2.5 and 0.2 mm glucose, respectively, vs. 5 or 10 mm glucose (P < 0.05). In contrast, glucose transporter-3 levels were not affected by incubation in various glucose concentrations.
Conclusions: These findings indicate that high glucose concentrations inhibit the invasiveness of HTR-8/SVneo cells by preventing uPA activation. Therefore, through its effects on uPA activity, glucose may be an important regulator of trophoblast invasiveness during implantation and placentation.