Exogenous laminin exhibits a unique vascular pattern in the brain via binding to dystroglycan and integrins

Fluids and Barriers of the CNS

Research

Jingsong Ruan¹  Yao Yao¹  Karen K. McKee²  Peter D. Yurchenco² 

[1] Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 8, 33612, Tampa, FL, USA;Department of Pathology and Laboratory Medicine, Rutgers University-Robert W. Johnson Medical School, Piscataway, NJ, USA;

关键词: Laminin;    Dystroglycan;    Integrins;    Vascular pattern;    Perivascular space;   

DOI  :  10.1186/s12987-022-00396-y

 received in 2022-08-16, accepted in 2022-11-28,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundUnlike other proteins that exhibit a diffusion pattern after intracerebral injection, laminin displays a vascular pattern. It remains unclear if this unique vascular pattern is caused by laminin-receptor interaction or laminin self-assembly.MethodsWe compared the distribution of various wild-type laminin isoforms in the brain after intracerebral injection. To determine what causes the unique vascular pattern of laminin in the brain, laminin mutants with impaired receptor-binding and/or self-assembly activities and function-blocking antibodies to laminin receptors were used. In addition, the dynamics of laminin distribution and elimination were examined at multiple time points after intracerebral injection.ResultsWe found that β2-containing laminins had higher affinity for the vessels compared to β1-containing laminins. In addition, laminin mutants lacking receptor-binding domains but not that lacking self-assembly capability showed substantially reduced vascular pattern. Consistent with this finding, dystroglycan (DAG1) function-blocking antibody significantly reduced the vascular pattern of wild-type laminin-111. Although failed to affect the vascular pattern when used alone, integrin-β1 function-blocking antibody further decreased the vascular pattern when combined with DAG1 antibody. EDTA, which impaired laminini-DAG1 interaction by chelating Ca2+, also attenuated the vascular pattern. Immunohistochemistry revealed that laminins were predominantly located in the perivascular space in capillaries and venules/veins but not arterioles/arteries. The time-course study showed that laminin mutants with impaired receptor-engaging activity were more efficiently eliminated from the brain compared to their wild-type counterparts. Concordantly, significantly higher levels of mutant laminins were detected in the cerebral-spinal fluid (CSF).ConclusionsThese findings suggest that intracerebrally injected laminins are enriched in the perivascular space in a receptor (DAG1/integrin)-dependent rather than self-assembly-dependent manner and eliminated from the brain mainly via the perivascular clearance system.

【 授权许可】

CC BY   
© The Author(s) 2022

【 图 表 】

Fig. 4