title: Cathepsin L acutely alters microvessel integrity within the neurovascular unit during focal cerebral ischemia.
abstract: During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage.
authors.affiliation: Department of Medicine (Division of Hematology) and Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Yu-Huan
authors.initials: YH
authors.lastname: Gu
authors.affiliation: Department of Medicine (Division of Hematology) and Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.|Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kanazawa
authors.affiliation: Department of Surgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Stephanie Y
authors.initials: SY
authors.lastname: Hung
authors.affiliation: Scripps Genomic Medicine, The Scripps Translational Science Institute, La Jolla, California, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Koziol
authors.affiliation: Department of Medicine (Division of Hematology) and Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Del Zoppo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology*; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000201:enzymology; D042783:Endothelial Cells / Q000201:enzymology; D002534:Hypoxia, Brain / Q000201:enzymology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000201:enzymology; D055806:Microvessels / Q000201:enzymology* / Q000473:pathology*; D000069336:Neurovascular Coupling; D010215:Papio
chemical_list: D002401:Cathepsin B; D056668:Cathepsin L; D020782:Matrix Metalloproteinases