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Rapid differential endogenous plasminogen activator expression after acute middle cerebral artery occlusion
1Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Background And Purpose:
During focal cerebral ischemia, the microvascular matrix (ECM), which participates in microvascular integrity, is degraded and lost when neurons are injured. Loss of microvascular basal lamina antigens coincides with rapid expression of select matrix metalloproteinases (MMPs). Plasminogen activators (PAs) may also play a role in ECM degradation by the generation of plasmin or by MMP activation.
Methods:
The endogenous expressions of tissue-type plasminogen activator (tPA), urokinase (uPA), and PA inhibitor-1 (PAI-1) were quantified in 10-microm frozen sections from ischemic and matched nonischemic basal ganglia and in the plasma of 34 male healthy nonhuman primates before and after middle cerebral artery occlusion (MCA:O).
Results:
Within the ischemic basal ganglia, tissue uPA activity and antigen increased significantly within 1 hour after MCA:O (2P<0.005). tPA activity transiently decreased 2 hours after MCA:O (2P=0.01) in concert with an increase in PAI-1 antigen (2P=0.001) but otherwise did not change. The transient decrease in free tPA antigen was marked by an increase in the tPA-PAI-1 complex (2P<0.001). No significant relations to neuronal injury or intracerebral hemorrhage were discerned.
Conclusions:
The rapid increase in endogenous PA activity is mainly due to significant increases in uPA, but not tPA, within the ischemic basal ganglia after MCA:O. This increase and an increase in PAI-1 coincided with latent MMP-2 generation and microvascular ECM degeneration but not neuronal injury.
Insights
Cerebral ischemia rapidly increases urokinase plasminogen activator (uPA) in the brain, contributing to microvascular matrix degradation. This process, involving PA inhibitor-1 (PAI-1), occurs independently of neuronal injury.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Focal cerebral ischemia causes microvascular matrix (ECM) degradation, impacting microvascular integrity.
- Loss of microvascular basal lamina antigens correlates with matrix metalloproteinase (MMP) expression.
- Plasminogen activators (PAs) may contribute to ECM degradation via plasmin generation or MMP activation.
Purpose of the Study:
- To quantify endogenous tissue-type plasminogen activator (tPA), urokinase (uPA), and PA inhibitor-1 (PAI-1) expressions in nonhuman primate brains during focal cerebral ischemia.
- To investigate the role of PAs in microvascular ECM degeneration following middle cerebral artery occlusion (MCA:O).
Main Methods:
- Quantification of tPA, uPA, and PAI-1 in 10-microm frozen sections of ischemic and nonischemic basal ganglia.
- Measurement of these factors in plasma of 34 male nonhuman primates before and after MCA:O.
Main Results:
- Significant increase in tissue uPA activity and antigen within 1 hour post-MCA:O.
- Transient decrease in tPA activity and increase in PAI-1 antigen 2 hours post-MCA:O.
- Increased tPA-PAI-1 complex observed, with no correlation to neuronal injury or hemorrhage.
Conclusions:
- Rapid increase in endogenous PA activity post-MCA:O is primarily driven by uPA, not tPA, in the ischemic basal ganglia.
- Increased uPA and PAI-1 coincide with latent MMP-2 generation and microvascular ECM degeneration.
- The observed microvascular changes are not directly linked to neuronal injury.