Glucocorticoids modify effects of TGF-β1 on multidrug resistance in the fetal blood-brain barrier

Abstract

Transforming growth factor-β1 (TGF-β1) increases P-glycoprotein (P-gp; encoded by Abcb1) activity in fetal brain endothelial cells (BECs). P-gp is important for fetal brain protection against xenobiotics including synthetic glucocorticoids (sGC). We hypothesized that antenatal sGC would modify P-gp responsiveness to TGF-β1 in fetal BECs. Pregnant guinea pigs were treated with dexamethasone or vehicle (N = 5/group) on gestational day (GD) 48–49 and BECs derived on GD50. In BECs from control fetuses, TGF-β1 increased Abcb1 mRNA and P-gp function, by approximately 5-fold and 55% respectively, as well as tight junction function. In contrast, TGF-β1 had no effect on these parameters in BECs from sGC-exposed fetuses. Moreover, levels of TGF-β1 responsive gene, Smad7, were increased 3-fold in BECs from control fetuses after TGF-β1 but not in sGC-exposed fetuses. In conclusion, antenatal sGC alters responsiveness to TGF-β1 in fetal BECs. This study has identified novel mechanisms by which TGF-β1 and sGC modulate fetal brain protection against xenobiotics and other P-gp substrates.

• Blood-brain barrier
• prenatal glucocorticoids
• TGF-β1
• multidrug resistance
• endothelial cell
• fetus

Declaration of interest

S.B., M.I., E.B., S.K., W.G., and S.G.M. have no conflicts of interest to declare.

This study was funded by the Canadian Institutes for Health Research (FRN-84220 to S.G.M. and W.G. and Doctoral Research Award to S.B.).