Adenosine Receptors and Angiogenesis

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See related article, pages 1130–1138 As originally hypothesized by Berne,1 adenosine is formed in the heart during hypoxia or ischemia and serves as a negative feedback signal to maintain oxygen delivery within a normal physiological range. Adenosine is formed by the metabolism of ATP and transported into the extracellular space by various nucleoside transport proteins.2 In a more localized manner that provides the opportunity for coordinated signaling with the diverse P2 purinoreceptor family that recognizes ATP and ADP, adenosine is also formed from the extracellular metabolism of adenine nucleotides released from stored granules (sympathetic nerves, platelets, mast cells) or through hemichannels (neutrophils, endothelial cells, epithelial cells) by ecto-apyrases and ecto-nucleotidases.3–5 Adenosine signals through activation of widely distributed cell surface G protein–coupled receptors, of which 4 different subtypes have been identified designated A1, A2A, A2B, and A3.6 By activating A2A receptors that are abundantly expressed in coronary vascular smooth muscle, adenosine generated under hypoxic conditions produces potent vasodilation thereby increasing nutrient and oxygen delivery. Although less appreciated, adenosine also serves to maintain tissue oxygenation in response to chronic ischemic/hypoxic stress by increasing the formation of new blood vessels; that is, by stimulating angiogenesis.7,8 Using adenosine receptor agonists or modulators of adenosine metabolism, an important role for adenosine has been established in in vivo models of angiogenesis.7,8 In cell culture systems, adenosine stimulates endothelial cell migration, proliferation, and tube formation,7–11 actions required for the formation of new capillary networks. This action occurs at concentrations of adenosine that are …