Published Online
on May 29, 2003

A more recent version of this article appeared on July 1, 2003

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Submitted on December 3, 2002
Accepted on January 15, 2003

Molecular Determinants of the Prothrombogenic and Inflammatory Phenotype Assumed by the Postischemic Cerebral Microcirculation

Mami Ishikawa MD, PhD; Dianne Cooper PhD; Janice Russell BS; James W. Salter MS; John H. Zhang MD, PhD; Anil Nanda MD; and D. Neil Granger PhD^*

From the Departments of Molecular and Cellular Physiology (M.I., D.C., J.R., J.W.S., D.N.G.) and Neurosurgery (J.H.Z., A.N.), Louisiana State University Health Sciences Center, Shreveport.

^* To whom correspondence should be addressed. E-mail: dgrang{at}lsuhsc.edu.

Background and Purpose--Circulating blood cells have been implicated in the pathogenesis of cerebral ischemia/reperfusion (I/R) injury and stroke. The objective of this study was to define the magnitude and molecular determinants of the platelet- and leukocyte-endothelial cell adhesive interactions induced by I/R in the mouse brain.

Methods--Bilateral common carotid artery occlusion was induced for 1 hour in C57BL/6 mice, followed by either 40 minutes or 4 hours of reperfusion. Fluorescent platelets were administered intravenously, and the frontal brain surface was observed with intravital fluorescence microscopy. Leukocyte-endothelial cell adhesion was monitored with the use of rhodamine-6G.

Results--Ischemia followed by 40 minutes of reperfusion resulted in the rolling (125.1±23.6/mm²) and firm adhesion (109.5±25.8/mm²) of leukocytes but not platelets in venules. However, with 4 hours of reperfusion, rolling (138.8±24.6/mm²) and firm adhesion (153.7±22.3/mm²) of platelets were detected, and this was accompanied by a more intense recruitment of rolling (374.5±54.6/mm²) and adherent (445.2±57.1/mm²) leukocytes. In mice deficient in either P-selectin (P-selectin^-/-) or intercellular adhesion molecule-1 (ICAM-1) (ICAM-1^-/-), the I/R-induced platelet-endothelial cell (by 80% and 60%, respectively) and leukocyte-endothelial cell (by 84% and 78%, respectively) interactions were significantly blunted compared with those of wild-type mice.

Conclusions--These findings indicate that I/R promotes the adhesion of both platelets and leukocytes in cerebral venules, with the accumulation of adherent leukocytes preceding the recruitment of platelets. Both P-selectin and ICAM-1 contribute to the inflammatory and prothrombogenic state induced by cerebral I/R.

Key words: cerebral ischemia • intercellular adhesion molecule-1 • leukocytes • platelets • selectins

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