PT  - JOURNAL ARTICLE
AU  - Sergey Ryzhov
AU  - Jennifer L. McCaleb
AU  - Anna E. Goldstein
AU  - Italo Biaggioni
AU  - Igor Feoktistov
TI  - Role of Adenosine Receptors in the Regulation of Angiogenic Factors and Neovascularization in Hypoxia
AID  - 10.1124/jpet.106.114850
DP  - 2007 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 565--572
VI  - 320
IP  - 2
4099  - http://jpet.aspetjournals.org/content/320/2/565.short
4100  - http://jpet.aspetjournals.org/content/320/2/565.full
SO  - J Pharmacol Exp Ther2007 Feb 01; 320
AB  - Because hypoxia increases extracellular adenosine levels and stimulates angiogenesis, we evaluated the relative roles of reduced oxygen concentrations and adenosine receptor activation in the production of angiogenic factors. In vitro, we analyzed the effects of hypoxia and adenosine on the secretion of angiogenic factors from human microvascular endothelial cells (HMEC-1). To study the effects of hypoxia alone, we scavenged adenosine from the hypoxic medium with adenosine deaminase, and we used the stable adenosine analog 5′-N-ethylcarboxamidoadenosine (NECA) to study the effects of stimulation of adenosine receptors. In the absence of adenosine, hypoxia stimulated vascular endothelial growth factor (VEGF) but not interleukin-8 (IL-8) secretion from HMEC-1. In contrast, NECA stimulated both VEGF and IL-8 secretion. VEGF secretion was increased 1.9 ± 0.04-fold with NECA (10 μM) and 1.7 ± 0.1-fold with hypoxia (5% O2) but 3.8 ± 0.1-fold when these two stimuli were combined. Thus, adenosine receptors act in a cooperative fashion with hypoxia to stimulate VEGF and induce IL-8 secretion not stimulated by hypoxia alone. In vivo, antagonism of adenosine receptors with caffeine abrogated VEGF up-regulation induced by local injection of NECA into the mouse hind limb and produced a 46% reduction of neovascularization in a mouse ischemic hind limb model. Our study suggests that adenosine actions are not redundant but rather are complementary to the direct effects of hypoxia. Stimulation of adenosine receptors not only contributes to the overall effect of hypoxia but also has additional actions in the regulation of angiogenic factors. Thus, adenosine receptors represent a potential therapeutic target for regulation of neovascularization. The American Society for Pharmacology and Experimental Therapeutics