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Inhibition of Human Trophoblast Invasiveness by High Glucose Concentrations

Department of Anatomy and Cell Biology, Queen’s University, Kingston, Ontario, Canada K7L 3N6

Address all correspondence and requests for reprints to: Dr. Charles H. Graham, Department of Anatomy and Cell Biology, Botterell Hall, 9th Floor, Queen’s University, Kingston, Ontario, Canada K7L 3N6. E-mail: grahamc{at}post.queensu.ca.

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.

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