Published Online
on March 28, 2005

A more recent version of this article appeared on April 5, 2005

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Submitted on August 17, 2004
Revised on November 18, 2004
Accepted on November 23, 2004

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, and 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.

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

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 • microcirculation • stroke

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Circulation 2005 111: 1567. [Full Text]

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