The extracellular matrix protein laminin α2 regulates the maturation and function of the blood-brain barrier.
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.
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651.
Michael J
MJ
Menezes
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651.
Freyja K
FK
McClenahan
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651.
Cindy V
http://orcid.org/0000-0003-2204-5341
CV
Leiton
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651.
Azeez
A
Aranmolate
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651.
Xiwei
X
Shan
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651 holly.colognato@stonybrook.edu.
Holly
H
Colognato
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000473:pathology; D001812:Blood-Brain Barrier / Q000254:growth & development* / Q000473:pathology / Q000502:physiology*; D049030:Dystroglycans / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D007797:Laminin / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D019108:Tight Junctions / Q000473:pathology
D000954:Antigens, Surface; D051401:Aquaporin 4; D051272:Glucose Transporter Type 1; D007797:Laminin; C095910:MECA-32 antigen, mouse; C102645:laminin alpha 2; D049030:Dystroglycans
astrocyte; blood–brain barrier; dystroglycan; gliovascular; laminin; pericyte