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(Stroke. 2003;34:1777.)
© 2003 American Heart Association, Inc.

Original Contributions

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 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.

Correspondence to D. Neil Granger, PhD, Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130-3932. 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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