Background and Objectives
Plasminogen appears to affect
brain inflammation, cell movement, fibrinolysis, neuronal excitotoxicity, and cell death. However, brain tissue and circulating blood
plasminogen may have different roles, and there is wide individual variation in blood
plasminogen levels. The aim of this study was to determine the integrated effect of blood
plasminogen levels on ischemic
brain injury. Methods We examined thromboembolic
stroke in mice with varying, experimentally determined, blood
plasminogen levels. Ischemic
brain injury, blood-brain barrier breakdown,
matrix metalloproteinase-9 expression and microvascular
thrombosis were determined. Results Within the range of normal variation,
plasminogen levels were strongly associated with ischemic
brain injury; higher blood
plasminogen levels had dose-related, protective effects. Higher
plasminogen levels were associated with increased dissolution of the middle cerebral artery
thrombus. Higher
plasminogen levels decreased blood-brain barrier breakdown,
matrix metalloproteinase-9 expression and microvascular
thrombosis in the ischemic brain. In
plasminogen-deficient mice, selective restoration of blood
plasminogen levels reversed the harmful effects of
plasminogen deficiency on ischemic
brain injury. Specific inhibition of
thrombin also reversed the effect of
plasminogen deficiency on ischemic injury by decreasing microvascular
thrombosis, blood-brain barrier breakdown, and
matrix metalloproteinase-9 expression. Conclusions Variation in blood
plasminogen levels, within the range seen in normal individuals, had marked effects on experimental ischemic
brain injury. Higher
plasminogen levels protected against ischemic
brain injury, and decreased blood-brain barrier breakdown,
matrix metalloproteinase-9 expression, and microvascular
thrombosis. The protective effects of blood
plasminogen appear to be mediated largely through a decrease in microvascular
thrombosis in the ischemic territory.