title: TGF-β1 regulation of multidrug resistance P-glycoprotein in the developing male blood-brain barrier.
abstract: P-glycoprotein (P-gp), an efflux transporter encoded by the abcb1 gene, protects the developing fetal brain. Levels of P-gp in endothelial cells of the blood-brain barrier (BBB) increase dramatically during the period of peak brain growth. This is coincident with increased release of TGF-β1 by astrocytes and neurons. Although TGF-β1 has been shown to modulate P-gp activity in a number of cell types, little is known about how TGF-β1 regulates brain protection. In the present study, we hypothesized that TGF-β1 increases abcb1 expression and P-gp activity in fetal and postnatal BBB in an age-dependent manner. We found TGF-β1 to potently regulate abcb1 mRNA and P-gp function. TGF-β1 increased P-gp function in brain endothelial cells (BECs) derived from fetal and postnatal male guinea pigs. These effects were more pronounced earlier in gestation when compared with BECs derived postnatally. To investigate the signaling pathways involved, BECs derived at gestational day 50 and postnatal day 14 were exposed to ALK1 and ALK5 inhibitors and agonists. Through inhibition of ALK5, we demonstrated that ALK5 is required for the TGF-β1 effects on P-gp function. Activation of ALK1, by the agonist BMP-9, produced similar results to TGF-β1 on P-gp function. However, TGF-β1 signaling through the ALK1 pathway is age-dependent as dorsomorphin, an ALK1 inhibitor, attenuated TGF-β1-mediated effects in BECs derived at postnatal day 14 but not in those derived at gestational day 50. In conclusion, TGF-β1 regulates P-gp at the fetal and neonatal BBB and both ALK5 and ALK1 pathways are implicated in the regulation of P-gp function. Aberrations in TGF-β1 levels at the developing BBB may lead to substantial changes in fetal brain exposure to P-gp substrates, triggering consequences for brain development.
authors.affiliation: Department of Physiology (S.B., M.I., E.B., M.J., S.G.M.), Obstetrics and Gynecology (S.G.M.), and Medicine (S.G.M.), Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and Department of Obstetrics and Gynecology (W.G.), and Cellular and Molecular Medicine (W.G.), Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Baello
authors.forename: Majid
authors.initials: M
authors.lastname: Iqbal
authors.forename: Enrrico
authors.initials: E
authors.lastname: Bloise
authors.forename: Mohsen
authors.initials: M
authors.lastname: Javam
authors.forename: William
authors.initials: W
authors.lastname: Gibb
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 / Q000254:growth & development / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D008297:Male; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053773:Transforming Growth Factor beta1