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Received for publication October 5, 2004.
Revised January 26, 2005.
Accepted for publication January 26, 2005.
Topical adenosine A2A 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 A2A receptor occupancy modulates expression of the anti-angiogenic matrix protein thrombospondin 1 (TSP1). We therefore determined whether A2A receptor occupation stimulates angiogenesis by modulating TSP1 secretion. Human microvascular endothelial cells (HMVEC) were treated with medium alone, CGS-21680 or MRE0094, selective A2A receptor agonists. TSP1 protein secretion was downregulated following treatment with the A2A agonists CGS-21680 or MRE0094 in a dose-dependent manner (EC50=6.65 nM or 0.23 µM, respectively). The selective A2A receptor antagonist ZM241385 but not the A1 and A2B receptor antagonists DPCPX, enprofylline and MRS 1706, completely abrogated the A2A receptor agonist-mediated effect on TSP1. Vascular tube formation by HMVEC was increased by adenosine A2A receptor agonists in a dose-dependent fashion (EC50= 0.1 µM for both) and this effect was reversed by the A2A antagonist. Moreover, in the presence of antibodies to TSP1 and CD36, the receptor for TSP1, the adenosine A2A receptor agonists stimulated no increase in vascular tube formation. These results indicate that the angiogenic effects of adenosine A2A receptor activation are, at least in part, due to suppression of TSP1 secretion.
Key words:
Adenosine, Angiogenesis
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