Published Online
on April 24, 2006

A more recent version of this article appeared on May 2, 2006

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Submitted on October 13, 2005
Revised on February 28, 2006
Accepted on March 2, 2006

CD73/Ecto-5'-Nucleotidase Protects Against Vascular Inflammation and Neointima Formation

Alma Zernecke MD, Kiril Bidzhekov PhD, Burcin Özüyaman MD, Line Fraemohs MSc, Elisa A. Liehn MD, Juliane M. Lüscher-Firzlaff MD, Bernhard Lüscher PhD, Jürgen Schrader MD, and Christian Weber MD^*

From the Institute of Molecular Cardiovascular Research (A.Z., K.B., B.Ö., L.F., E.A.L., C.W.) and the Division of Biochemistry and Molecular Biology (J.M.L.-F., B.L.), Rheinisch-Westfälische Technisch Hochschule (RWTH University), Aachen, Germany, and the Institute of Cardiovascular Physiology (B.Ö., J.S.), Heinrich-Heine University, Düsseldorf, Germany.

^* To whom correspondence should be addressed. E-mail: cweber{at}ukaachen.de.

Background--Although CD73/ecto-5'-nucleotidase has been implicated in maintaining vasoprotection, its role in regulating endothelial adhesion molecule or inflammatory monocyte recruitment (eg, in the context of vascular injury) remains to be defined.

Methods and Results--Compared with wild-type mice, CD73-deficient (CD73^-/-) mice exhibit increased luminal staining and protein and transcript expression for vascular cell adhesion molecule (VCAM)-1 in carotid arteries. In vitro, aortic endothelial cells (ECs) from CD73^-/- mice display an upregulation of mRNA and protein expression of VCAM-1, associated with increased nuclear factor (NF)-B activity, as determined by chromatin cross-linking and immunoprecipitation or quantitative p65 binding assays. CD73^-/- ECs and carotid arteries perfused ex vivo supported increased monocyte arrest under flow conditions, which was mediated by ₄₁ integrin. After wire injury of carotid arteries, CD73 expression and activity were upregulated in wild-type mice, whereas neointimal plaque formation and macrophage content were increased in CD73^-/- mice versus wild-type mice, concomitant with elevated NF-B activation, luminal VCAM-1 expression, and soluble VCAM-1 concentrations. In contrast, reconstitution of wild-type mice with CD73^-/- versus CD73^+/+ BM did not significantly exacerbate neointima formation. Treatment with the specific A_2A receptor agonist ATL-146e reversed the increased VCAM-1 transcript and protein expression in CD73^-/- ECs and inhibited monocyte arrest on CD73^-/- ECs. Continuous infusion of ATL-146e prevented neointima formation in CD73^-/- mice.

Conclusions--Our data epitomize the importance of vascular CD73 in limiting endothelial activation and monocyte recruitment via generation of adenosine acting through the A_2A receptor, providing a molecular basis for therapeutic protection against vascular inflammation and neointimal hyperplasia.

Key words: cell adhesion molecules • endothelium • lesion • leukocytes

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