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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2024-2035.
Prepublished online as a Blood First Edition Paper on December 4, 2007; DOI 10.1182/blood-2007-10-117044.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
A2B adenosine receptor dampens hypoxia-induced vascular leak
Tobias Eckle1,
Marion Faigle1,
Almut Grenz2,
Stefanie Laucher1,
Linda F. Thompson3, and
Holger K. Eltzschig1,4
1 Departments of Anesthesiology and Intensive Care Medicine and
2 Pharmacology and Toxicology, Tübingen University Hospital, Tübingen, Germany;
3 Immunobiology and Cancer Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City; and
4 Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Denver
Extracellular adenosine has been implicated in adaptation to hypoxia and previous studies demonstrated a central role in vascular responses. Here, we examined the contribution of individual adenosine receptors (ARs: A1AR/A2AAR/A2BAR/A3AR) to vascular leak induced by hypoxia. Initial profiling studies revealed that siRNA-mediated repression of the A2BAR selectively increased endothelial leak in response to hypoxia in vitro. In parallel, vascular permeability was significantly increased in vascular organs of A2BAR–/–-mice subjected to ambient hypoxia (8% oxygen, 4 hours; eg, lung: 2.1 ± 0.12-fold increase). By contrast, hypoxia-induced vascular leak was not accentuated in A1AR–/–-, A2AAR–/–-, or A3AR–/–-deficient mice, suggesting a degree of specificity for the A2BAR. Further studies in wild type mice revealed that the selective A2BAR antagonist PSB1115 resulted in profound increases in hypoxia-associated vascular leakage while A2BAR agonist (BAY60-6583 [2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)-. phenyl]pyridin-2-ylsulfanyl]acetamide]) treatment was associated with almost complete reversal of hypoxia-induced vascular leakage (eg, lung: 2.0 ± 0.21-fold reduction). Studies in bone marrow chimeric A2BAR mice suggested a predominant role of vascular A2BARs in this response, while hypoxia-associated increases in tissue neutrophils were, at least in part, mediated by A2BAR expressing hematopoietic cells. Taken together, these studies provide pharmacologic and genetic evidence for vascular A2BAR signaling as central control point of hypoxia-associated vascular leak.

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