CD73/ecto-5'-nucleotidase protects against vascular inflammation and neointima formation.
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.


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)-kappaB 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 alpha(4beta1) 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-kappaB 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 A2A 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 A2A receptor, providing a molecular basis for therapeutic protection against vascular inflammation and neointimal hyperplasia.
Zernecke
Alma
A
Institute of Molecular Cardiovascular Research, Rheinisch-Westfälische Technisch Hochschule, Aachen, Germany.
Bidzhekov
Kiril
K
Ozüyaman
Burcin
B
Fraemohs
Line
L
Liehn
Elisa A
EA
Lüscher-Firzlaff
Juliane M
JM
Lüscher
Bernhard
B
Schrader
Jürgen
J
Weber
Christian
C
D015720:5'-Nucleotidase / Q000502:physiology*; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology; D006965:Hyperplasia; D039041:Integrin alpha4beta1 / Q000502:physiology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D017539:Tunica Intima / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology; D014657:Vasculitis / Q000517:prevention & control*
D039041:Integrin alpha4beta1; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D015720:5'-Nucleotidase