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Pro‐angiogenic role of adenosine receptors in hypoxia
Author(s) -
Ryzhov Sergey,
McCaleb Jennifer L.,
Goldstein Anna E.,
Zaynagetdinov Rinat,
Biaggioni Italo,
Feoktistov Igor
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1162-d
Subject(s) - adenosine , adenosine receptor , angiogenesis , adenosine a3 receptor , adenosine deaminase , hypoxia (environmental) , endocrinology , medicine , adenosine a1 receptor , purinergic signalling , receptor , adenosine receptor antagonist , downregulation and upregulation , vascular endothelial growth factor , secretion , chemistry , caffeine , biology , vegf receptors , biochemistry , oxygen , agonist , organic chemistry , gene
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 , hypoxia alone (adenosine deaminase added to culture media) stimulated VEGF but not IL‐8 secretion from human microvascular endothelial cells HMEC‐1. In contrast, the stable adenosine analog 5′‐N‐ethylcarboxamidoadenosine (NECA) stimulated both VEGF and IL‐8 secretion. VEGF secretion increased by 1.9±0.04‐fold with 10 μM NECA, and by 1.7±0.1‐fold with 5% O 2 hypoxia, but by 3.8±0.1‐fold when these two stimuli were combined. Thus, adenosine acts in a cooperative fashion with hypoxia to stimulate VEGF, and induces IL‐8 secretion not stimulated by hypoxia alone. In vivo , antagonism of adenosine receptors with caffeine abrogated VEGF upregulation induced by local injection of NECA into the mouse hindlimb and produced a 46% reduction of neovascularization in a mouse ischemic hindlimb model. Thus, adenosine receptors represent a potential therapeutic target for regulation of neovascularization. (Support: NIH).