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ORIGINAL ARTICLE

Adenosine A_2A Receptor Stimulation Increases Angiogenesis by Down-Regulating Production of the Antiangiogenic Matrix Protein Thrombospondin 1

Department of Medicine, New York University School of Medicine, New York, New York (A.D., C.V.-V., S.G., M.C.M., C.C.C., B.N.C.); and Immunology and Inflammation Center, North Shore-LIJ Research Institute, North Shore University Hospital, Manhasset, New York (C.C.C.)

Abstract

Topical adenosine A_2A receptor agonists promote wound healing by, among other effects, increasing microvessel formation. Results of representational display analysis of human umbilical vein endothelial cells suggested that A_2A receptor occupancy modulates expression of the antiangiogenic matrix protein thrombospondin 1 (TSP1). We therefore determined whether A_2A receptor occupation stimulates angiogenesis by modulating TSP1 secretion. Human microvascular endothelial cells (HMVEC) were treated with medium alone, 2-p-[2-carboxyethyl] phenethyl-amino-5'-N-ethylcarboxamido-adenosine (CGS-21680), or 2-[2-(4-chlorophenyl)ethoxy]adenosine (MRE0094), selective A_2A receptor agonists. TSP1 protein secretion was down-regulated after treatment with the A_2A agonists CGS-21680 or MRE0094 in a dose-dependent manner (EC₅₀ = 6.65 nM and 0.23 µM respectively). The selective A_2A receptor antagonist 4-{2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol (ZM241385) but not the A1 and A_2B receptor antagonists diphenylcyclopentylxanthine, enprofylline, and N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS1706) completely abrogated the A_2A receptor agonist-mediated effect on TSP1. Vascular tube formation by HMVEC was increased by adenosine A_2A receptor agonists in a dose-dependent fashion (EC₅₀ = 0.1 µM for both), and this effect was reversed by the A_2A antagonist. Moreover, in the presence of antibodies to TSP1 and CD36, the receptor for TSP1, the adenosine A_2A receptor agonists stimulated no increase in vascular tube formation. These results indicate that the angiogenic effects of adenosine A_2A receptor activation are, at least in part, caused by the suppression of TSP1 secretion.

Address correspondence to: Dr. Bruce N. Cronstein, NYU School of Medicine, 550 1st Avenue, New Bellevue 16N1, New York, NY 10016. E-mail: cronsb01{at}med.nyu.edu

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