Disruption of astrocyte–vascular coupling and the blood–brain barrier by invading glioma cells

• Published in: Nature communications 2014-06, Vol.5 (1), p.4196-4196, Article 4196
• Main Authors: Watkins, Stacey, Robel, Stefanie, Kimbrough, Ian F., Robert, Stephanie M., Ellis-Davies, Graham, Sontheimer, Harald
• Format: Article
• Language: English
• Subjects: 13/51; 14/19; 14/28; 14/34; 14/69; 631/378/1341; 631/378/2607; 631/67/1922; 631/80/84/2336; 64/60; Animals; Astrocytes - metabolism; Astrocytes - pathology; Biological Transport; Blood Vessels - metabolism; Blood-Brain Barrier - metabolism; Brain - blood supply; Brain - metabolism; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Calcium - metabolism; Female; Glioma - metabolism; Glioma - pathology; Humanities and Social Sciences; Humans; Male; Mice; Mice, SCID; multidisciplinary; Neoplasm Invasiveness; Potassium - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5196

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. Astrocytic endfeet maintain endothelial tight junctions that form the blood–brain barrier (BBB), which can be damaged by invading gliomas. Here, the authors show that this damage is due to the association of gliomas with existing vessels and the displacement of astrocytic endfeet.