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(Circulation. 2005;111:1690-1696.)
© 2005 American Heart Association, Inc.

Stroke

CD40/CD40 Ligand Signaling in Mouse Cerebral Microvasculature After Focal Ischemia/Reperfusion

Mami Ishikawa, MD, PhD; Thorsten Vowinkel, MD; Karen Y. Stokes, PhD; Thiruma V. Arumugam, PhD; Gokhan Yilmaz, MD; Anil Nanda, MD; D. Neil Granger, PhD

From the Departments of Molecular and Cellular Physiology (M.I., T.V., K.Y.S., T.V.A., G.Y., D.N.G.) and Neurosurgery (A.N.), Louisiana State University Health Sciences Center, Shreveport, La.

Correspondence to D. Neil Granger, PhD, Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932. E-mail dgrang{at}lsuhsc.edu

Received August 17, 2004; revision received November 18, 2004; accepted November 23, 2004.

Background— CD40/CD40 ligand (CD40L) signaling contributes to proinflammatory and prothrombogenic responses in the vasculature. CD40/CD40L expression is elevated in patients after a transient ischemic attack or stroke. The purpose of this study was to investigate the role of CD40/CD40L signaling in cerebral microvascular dysfunction and tissue injury response to middle cerebral artery occlusion (MCAO) and reperfusion.

Methods and Results— Intravital fluorescence microscopy was used to visualize the cerebral microcirculation of wild-type (WT), CD40-deficient, and CD40L-deficient mice subjected to 1-hour MCAO and 4-hour reperfusion. The adhesion of platelets and of leukocytes and vascular permeability were measured in postcapillary venules after 4-hour and 1-hour reperfusions, respectively. Cerebral infarct volume was analyzed 24 hours after reperfusion. Platelet and leukocyte adhesion was elevated and blood/brain barrier function was compromised by MCAO in WT mice. Blood cell recruitment and increased permeability were blunted in both CD40-deficient and CD40L-deficient mice. Infarct volume was also reduced in CD40- and CD40L-deficient mice compared with WT mice.

Conclusions— Our findings indicate that CD40/CD40L signaling contributes to inflammatory and prothrombogenic responses and brain infarction induced by MCAO and reperfusion. The CD40/CD40L dyad may play a significant pathogenic role in the acute phase of ischemic stroke.

Key Words: platelets • leukocytes • cerebral ischemia • microcirculationstroke

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