title: 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.
authors.affiliation: a Department of Physiology , University of Toronto , Toronto , ON , Canada .
authors.forename: Stephanie
authors.initials: S
authors.lastname: Baello
authors.affiliation: a Department of Physiology , University of Toronto , Toronto , ON , Canada .
authors.forename: Majid
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: a Department of Physiology , University of Toronto , Toronto , ON , Canada .
authors.forename: Samantha
authors.initials: S
authors.lastname: Kearney
authors.affiliation: a Department of Physiology , University of Toronto , Toronto , ON , Canada .
authors.forename: Shikah
authors.initials: S
authors.lastname: Kuthiala
authors.affiliation: b Department of Morphology , Federal University of Minas Gerais , Belo Horizonte , Brazil .
authors.forename: Enrrico
authors.initials: E
authors.lastname: Bloise
authors.affiliation: c Department of Obstetrics and Gynecology , and Cellular and Molecular Medicine, University of Ottawa , Ottawa , ON , Canada .
authors.forename: William
authors.initials: W
authors.lastname: Gibb
authors.affiliation: a Department of Physiology , University of Toronto , Toronto , ON , Canada .|d Department of Obstetrics and Gynecology , University of Toronto , Toronto , ON , Canada , and.|e Department of Medicine , Faculty of Medicine, University of Toronto , Toronto , ON , Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006168:Guinea Pigs; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D012333:RNA, Messenger; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1
keywords: Blood-brain barrier; TGF-β1; endothelial cell; fetus; multidrug resistance; prenatal glucocorticoids