Inhibition of human trophoblast invasiveness by high glucose concentrations.
BACKGROUND
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.
Belkacemi
Louiza
L
Department of Anatomy and Cell Biology, Botterell Hall, 9th Floor, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Lash
Gendie E
GE
Macdonald-Goodfellow
Shannyn K
SK
Caldwell
Jason D
JD
Graham
Charles H
CH
D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D009004:Monosaccharide Transport Proteins; D009419:Nerve Tissue Proteins; C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C495677:SLC2A1 protein, human; C495687:SLC2A3 protein, human; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases; D005947:Glucose