title: Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator.
abstract: Impaired wound healing, as it occurs in diabetes mellitus or long-term corticoid treatment, is commonly associated with disability, diminished quality of life, and high economic costs. Selective agonists of the A2A receptor subtype of adenosine, an endogenous regulator of inflammation, promote tissue repair in animal models, both healthy and with impaired healing. Plasmin-mediated proteolysis of fibrin and other matrix proteins is essential for cell migration at sites of injury. Since adenosine A2A receptor activation increases plasminogen activator release from macrophages and mast cells, we studied the effect of a selective agonist, CGS-21680, on full-thickness excisional wound closure in wild-type, urokinase plasminogen activator (uPA)-deficient, and tissue plasminogen activator (tPA)-deficient mice. Wound closure was impaired in tPA- and uPA-deficient mice as compared with wild-type mice, and topical application of CGS-21680 significantly increased the rate at which wounds closed in wild-type mice and uPA-deficient mice, but not in tPA-deficient mice. Immunostaining of tissue sections showed that tPA was present in endothelial cells and histiocytes by day 3 post-wound and also by day 6. In contrast, uPA was more prominent in these cell types only by day 6 post-wound. Our results confirm that plasminogen activation contributes to wound repair and are consistent with the hypothesis that adenosine A2A receptor activation promotes wound closure by a mechanism that depends upon tPA, but not uPA. Moreover, our results suggest that topical adenosine A2A receptor agonists may be useful in promotion of wound closure in patients with impaired wound healing.
authors.affiliation: Department of Medicine, New York University School of Medicine, 550 First Avenue, MSB251, New York, NY, 10016, USA. m.carmen.montesinos@uv.es.|Instituto de Reconocimiento Molecular y Desarrollo Tecnológico, Centro Mixto Universidad Politécnica de Valencia, Universidad de Valencia, Valencia, Spain. m.carmen.montesinos@uv.es.|Department de Farmacologia, Universitat de València, Ave. Vicent Andrès Estellès s/n, 46100 Burjassot, Valencia, Spain. m.carmen.montesinos@uv.es.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Montesinos
authors.affiliation: Department of Medicine, New York University School of Medicine, 550 First Avenue, MSB251, New York, NY, 10016, USA.
authors.forename: Avani
authors.initials: A
authors.lastname: Desai-Merchant
authors.affiliation: Department of Medicine, New York University School of Medicine, 550 First Avenue, MSB251, New York, NY, 10016, USA.
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058908:Adenosine A2 Receptor Agonists / Q000008:administration & dosage*; D000279:Administration, Cutaneous; D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006644:Histiocytes / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010627:Phenethylamines / Q000008:administration & dosage*; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*; D014950:Wounds, Penetrating / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D058908:Adenosine A2 Receptor Agonists; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D000241:Adenosine
keywords: adenosine A2A receptors; animal models; plasminogen activator; wound healing