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: Yu-Huan Gu, Masato Kanazawa, Stephanie Y Hung, Xiaoyun Wang, Shunichi Fukuda, James A Koziol, Gregory J Del Zoppo
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 35 Issue 11 Pg. 1888-900 (Nov 2015) ISSN: 1559-7016 [Electronic] United States
• PMID: 26198177 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cathepsin B
• Cathepsin L
• Matrix Metalloproteinases

Topics

• Animals
• Astrocytes (enzymology)
• Brain Ischemia (enzymology, pathology)
• Cathepsin B (genetics, metabolism)
• Cathepsin L (genetics, metabolism)
• Cells, Cultured
• Cerebral Hemorrhage (enzymology)
• Endothelial Cells (enzymology)
• Hypoxia, Brain (enzymology)
• Male
• Matrix Metalloproteinases (metabolism)
• Mice
• Mice, Inbred C57BL
• Microglia (enzymology)
• Microvessels (enzymology, pathology)
• Neurovascular Coupling
• Papio