RT Journal Article
SR Electronic
T1 The Extracellular Matrix Protein Laminin α2 Regulates the Maturation and Function of the Blood–Brain Barrier
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 15260
OP 15280
DO 10.1523/JNEUROSCI.3678-13.2014
VO 34
IS 46
A1 Michael J. Menezes
A1 Freyja K. McClenahan
A1 Cindy V. Leiton
A1 Azeez Aranmolate
A1 Xiwei Shan
A1 Holly Colognato
YR 2014
UL http://www.jneurosci.org/content/34/46/15260.abstract
AB Laminins are major constituents of the gliovascular basal lamina of the blood–brain barrier (BBB); however, the role of laminins in BBB development remains unclear. Here we report that Lama2−/− mice, lacking expression of the laminin α2 subunit of the laminin-211 heterotrimer expressed by astrocytes and pericytes, have a defective BBB in which systemically circulated tracer leaks into the brain parenchyma. The Lama2−/− vascular endothelium had significant abnormalities, including altered integrity and composition of the endothelial basal lamina, inappropriate expression of embryonic vascular endothelial protein MECA32, substantially reduced pericyte coverage, and tight junction abnormalities. Additionally, astrocytic endfeet were hypertrophic and lacked appropriately polarized aquaporin4 channels. Laminin-211 appears to mediate these effects at least in part by dystroglycan receptor interactions, as preventing dystroglycan expression in neural cells led to a similar set of BBB abnormalities and gliovascular disturbances, which additionally included perturbed vascular endothelial glucose transporter-1 localization. These findings provide insight into the cell and molecular changes that occur in congenital muscular dystrophies caused by Lama2 mutations or inappropriate dystroglycan post-translational modifications, which have accompanying brain abnormalities, including seizures. Our results indicate a novel role for laminin–dystroglycan interactions in the cooperative integration of astrocytes, endothelial cells, and pericytes in regulating the BBB.