Cathepsin L acutely alters microvessel integrity within the neurovascular unit during focal cerebral ischemia

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Focal cerebral ischemia causes microvessel basal lamina degradation, leading to edema and hemorrhage.
• Matrix metalloproteinases (MMPs) were previously implicated, but other proteases likely contribute.
• The precise mechanisms of microvessel matrix loss during ischemia require further elucidation.

Purpose of the Study:

• To define the role of active cathepsin L in microvessel basal lamina degradation during focal cerebral ischemia.
• To investigate the cellular sources and regulation of cathepsin L activity in the ischemic brain.
• To explore the interaction between cathepsin L and MMPs in the context of ischemic brain injury.

Main Methods:

• Analysis of cerebral tissues from a non-human primate focal ischemia model.
• In vitro studies using primary murine brain endothelial cells, astrocytes, and microglia.
• Development of a novel ex vivo assay to assess microvessel matrix degradation.

Main Results:

• Active cathepsin L, but not cathepsin B, appeared in the ischemic core within 2 hours of ischemia onset.
• Ischemia induced cathepsin L activity primarily in microglia, with increased release in the acidic ischemic environment.
• Released microglial cathepsin L degraded microvessel matrix and interacted with MMP activity.

Conclusions:

• Microglial cathepsin L release is a key mechanism for microvessel matrix degradation during focal cerebral ischemia.
• Cathepsin L's interaction with MMPs contributes to microvessel injury and hemorrhage.
• Targeting cathepsin L may offer therapeutic strategies to mitigate ischemic brain damage.