Cerebral microvascular obstruction by fibrin is associated with upregulation of PAI-1 acutely after onset of focal embolic ischemia in rats

Citation
Zg. Zhang et al., Cerebral microvascular obstruction by fibrin is associated with upregulation of PAI-1 acutely after onset of focal embolic ischemia in rats, J NEUROSC, 19(24), 1999, pp. 10898-10907
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROSCIENCE
ISSN journal
0270-6474 → ACNP
Volume
19
Issue
24
Year of publication
1999
Pages
10898 - 10907
Database
ISI
SICI code
0270-6474(199912)19:24<10898:CMOBFI>2.0.ZU;2-#
Abstract
The mechanisms underlying cerebral microvascular perfusion deficit resultin g from occlusion of the middle cerebral artery (MCA) require elucidation. W e, therefore, tested the hypothesis that intravascular fibrin deposition in situ directly obstructs cerebral microcirculation and that local changes i n type 1 plasminogen activator inhibitor (PAI-1) gene expression contribute to intravascular fibrin deposition after embolic MCA occlusion. Using lase r-scanning confocal microscopy (LSCM) in combination with immunofluorescent staining, we simultaneously measured in three dimensions the distribution of microvascular plasma perfusion deficit and fibrin(ogen) immunoreactivity in a rat model of focal cerebral embolic ischemia (n = 12). In addition, u sing in situ hybridization and immunostaining, we analyzed expression of PA I-1 in ischemic brain (n = 13). A significant (p < 0.05) reduction of cereb ral microvascular plasma perfusion accompanied a significant (p < 0.05) inc rease of intravascular and extravascular fibrin deposition in the ischemic lesion. Microvascular plasma perfusion deficit and fibrin deposition expand ed concomitantly from the subcortex to the cortex during 1 and 4 hr of embo lic MCA occlusion. Three-dimensional analysis revealed that intravascular f ibrin deposition directly blocks microvascular plasma perfusion. Vascular p lugs contained erythrocytes, polymorphonuclear leukocytes, and platelets en meshed in fibrin. In situ hybridization demonstrated induction of PAI-1 mRN A in vascular endothelial cells in the ischemic region at 1 hr of ischemia. PAI-1 mRNA significantly increased at 4 hr of ischemia. Immunohistochemica l staining showed the same pattern of increased PAI-1 antigen in the endoth elial cells. These data demonstrate, for the first time, that progressive i ntravascular fibrin deposition directly blocks cerebral microvascular plasm a perfusion in the ischemic region during acute focal cerebral embolic isch emia, and upregulation of the PAI-1 gene in the ischemic lesion may foster fibrin deposition through suppression of fibrinolysis.