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(American Journal of Pathology. 2002;160:2009-2018.)
© 2002 American Society for Investigative Pathology

Regular Articles

Adenosine Promotes Wound Healing and Mediates Angiogenesis in Response to Tissue Injury Via Occupancy of A_2A Receptors

M. Carmen Montesinos^*, Avani Desai^*, Jiang-Fan Chen, Herman Yee^*, Michael A. Schwarzschild, J. Stephen Fink and Bruce N. Cronstein^*

From the Department of Medicine,^*New York University School of Medicine, New York, New York; and the Department of Neurology,Molecular Neurobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Recent evidence indicates that topical application of adenosine A_2A receptor agonists, unlike growth factors, increases the rate at which wounds close in normal animals and promotes wound healing in diabetic animals as well as growth factors, yet neither the specific adenosine receptor involved nor the mechanism(s) by which adenosine receptor occupancy promotes wound healing have been fully established. To determine which adenosine receptor is involved and whether adenosine receptor-mediated stimulation of angiogenesis plays a role in promotion of wound closure we compared the effect of topical application of the adenosine receptor agonist CGS-21680 (2-p-[2-carboxyethyl]phenethyl-amino-5'-N-ethylcarboxamido-adenosine) on wound closure and angiogenesis in adenosine A_2A receptor knockout mice and their wild-type littermates. There was no change in the rate of wound closure in the A_2A receptor knockout mice compared to their wild-type littermates although granulation tissue formation was nonhomogeneous and there seemed to be greater inflammation at the base of the wound. Topical application of CGS-21680 increased the rate of wound closure and increased the number of microvessels in the wounds of wild-type mice but did not affect the rate of wound closure in A_2A receptor knockout mice. Similarly, in a model of internal trauma and repair (murine air pouch model), endogenously produced adenosine released into areas of internal tissue injury stimulates angiogenesis because there was a marked reduction in blood vessels in the walls of healing air pouches of A_2A receptor knockout mice compared to their wild-type controls. Inflammatory vascular leakage and leukocyte accumulation in the inflamed air pouch were similarly reduced in the A_2A receptor knockout mice reflecting the reduced vascularity. Thus, targeting the adenosine A_2A receptor is a novel approach to promoting wound healing and angiogenesis in normal individuals and those suffering from chronic wounds.

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