title: Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells.
abstract: Astrocytic endfeet cover the entire cerebral vasculature and serve as exchange sites for ions, metabolites and energy substrates from the blood to the brain. They maintain endothelial tight junctions that form the blood-brain barrier (BBB) and release vasoactive molecules that regulate vascular tone. Malignant gliomas are highly invasive tumours that use the perivascular space for invasion and co-opt existing vessels as satellite tumour form. Here we use a clinically relevant mouse model of glioma and find that glioma cells, as they populate the perivascular space of preexisting vessels, displace astrocytic endfeet from endothelial or vascular smooth muscle cells. This causes a focal breach in the BBB. Furthermore, astrocyte-mediated gliovascular coupling is lost, and glioma cells seize control over the regulation of vascular tone through Ca(2+)-dependent release of K(+). These findings have important clinical implications regarding blood flow in the tumour-associated brain and the ability to locally deliver chemotherapeutic drugs in disease.
authors.affiliation: 1] Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, 1719 6th Avenue South, CIRC 425, Birmingham, Alabama 35294, USA [2].
authors.forename: Stacey
authors.initials: S
authors.lastname: Watkins
authors.affiliation: 1] Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, 1719 6th Avenue South, CIRC 425, Birmingham, Alabama 35294, USA [2].
authors.forename: Stefanie
authors.initials: S
authors.lastname: Robel
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, 1719 6th Avenue South, CIRC 425, Birmingham, Alabama 35294, USA.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Kimbrough
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, 1719 6th Avenue South, CIRC 425, Birmingham, Alabama 35294, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Robert
authors.affiliation: Department of Neuroscience, Mount Sinai School of Medicine, 1468 Madison Avenue, Annenberg Building Floor Ann22, New York, New York 10029, USA.
authors.forename: Graham
authors.initials: G
authors.lastname: Ellis-Davies
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, 1719 6th Avenue South, CIRC 425, Birmingham, Alabama 35294, USA.
authors.forename: Harald
authors.initials: H
authors.lastname: Sontheimer
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D001808:Blood Vessels / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011188:Potassium / Q000378:metabolism
chemical_list: D011188:Potassium; D002118:Calcium