title: Astrocyte-mediated regulation of multidrug resistance p-glycoprotein in fetal and neonatal brain endothelial cells: age-dependent effects.
abstract: Brain endothelial cells (BECs) form a major component of the blood-brain barrier (BBB). In late gestation, these cells express high levels of the multidrug transporter p-glycoprotein (P-gp; encoded by Abcb1), which prevents the passage of an array of endogenous factors and xenobiotics into the fetal brain. P-gp levels in the BECs increase dramatically in late gestation, coincident with astrocyte differentiation. However, the role of astrocytes in modulating P-gp in the developing BBB is unknown. We hypothesized that factors produced by astrocytes positively regulate P-gp in BECs. Astrocytes and BECs were isolated from fetal and postnatal guinea pigs. Levels of Abcb1 mRNA and P-gp were increased in BECs co-cultured with astrocytes compared to BECs in monoculture. Moreover, postnatal astrocytes enhanced P-gp function in fetal BECs but fetal astrocytes had no effect on postnatal BECs. These effects were dependent on secreted proteins with a molecular weight in the range of 3-100 kDa. LC/MS-MS revealed significant differences in proteins secreted by fetal and postnatal astrocytes. We propose that astrocytes are critical modulators of P-gp at the developing BBB. As such, aberrations in astrocyte maturation, observed in neurodevelopmental disorders, will likely decrease P-gp at the BBB. This would allow increased transfer of P-gp endogenous and exogenous substrates into the brain, many of which have neurodevelopmental consequences.
authors: Department of Physiology, Faculty of Medicine University of Toronto, Toronto, Ontario, Canada s.baello@mail.utoronto.ca.
authors: Stephanie
authors: S
authors: Baello
authors: Department of Physiology, Faculty of Medicine University of Toronto, Toronto, Ontario, Canada.
authors: Majid
authors: M
authors: Iqbal
authors: Department of Obstetrics and Gynecology, Faculty of Medicine University of Ottawa, Ottawa, Ontario, Canada.|Department of Cellular and Molecular Medicine, Faculty of Medicine University of Ottawa, Ottawa, Ontario, Canada.
authors: William
authors: W
authors: Gibb
authors: Department of Physiology, Faculty of Medicine University of Toronto, Toronto, Ontario, Canada.|Department of Obstetrics and Gynecology, Faculty of Medicine University of Toronto, Toronto, Ontario, Canada.|Department of Medicine, Faculty of Medicine University of Toronto, Toronto, Ontario, Canada.
authors: Stephen G
authors: SG
authors: Matthews
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D001921:Brain / Q000166:cytology* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D047109:Fetal Development / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D023421:Models, Animal; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C513055:ABCB1 protein, human
keywords: Astrocytes; P‐glycoprotein; blood–brain barrier; brain endothelial cells; fetus; glial cells