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.

Microglia and Monocytes/Macrophages Polarization Reveal Novel Therapeutic Mechanism against Stroke

“…In normal adult brain, chondroitin sulfate proteoglycan, a component of the extracellular matrix, has been reported to inhibit axonal outgrowth [ 82 ], and is shown to be cleaved and degraded by MMP-9 [ 83 ]. Microglia is the main source of MMP-9 [ 84 ] and cathepsin L after ischemia [ 85 ]. These proteinases might degrade the extracellular matrix and prompt axonal outgrowth.…”

Melatonin ameliorates hypoglycemic stress‐induced brain endothelial tight junction injury by inhibiting protein nitration of TP53‐induced glycolysis and apoptosis regulator

“…Brain microvascular endothelial cells form a barrier between the blood and the central nervous system that is critical for normal brain function . This blood‐brain barrier (BBB) integrity is achieved primarily through the presence of tight and adherent junctions between astrocyte end‐feet encircling endothelial cells in cerebrovascular capillaries that maintaining the central nervous system homeostasis .…”

Review of Alterations in Perlecan-Associated Vascular Risk Factors in Dementia

“…Stroke results from the disruption of blood flow to the brain due to the narrowing or occlusion of a vessel (ischemic) or to the weakening of the vessel wall (hemorrhagic). Perlecan was found to be lower in non-human primate models of focal cerebral ischemia [63,169], whereas DV has been demonstrated to increase in rodent models of stroke (endothelin-1 and tandem common carotid artery occlusion and distal middle cerebral artery occlusion) [18]. The therapeutic potential of recombinant DV after ischemic stroke has been demonstrated by us and others [18,40].…”