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(American Journal of Pathology. 2002;160:2231-2244.)
© 2002 American Society for Investigative Pathology

Regular Articles

Synergistic Up-Regulation of Vascular Endothelial Growth Factor Expression in Murine Macrophages by Adenosine A2A Receptor Agonists and Endotoxin

Samuel Joseph Leibovich*, Jiang-Fan Chen{dagger}, Grace Pinhal-Enfield*, Paula C. Belem*, Genie Elson*, Anthony Rosania*, Madhuri Ramanathan*, Carmen Montesinos{ddagger}, Marlene Jacobson§, Michael A. Schwarzschild{dagger}, J. Stephen Fink{dagger} and Bruce Cronstein{ddagger}

From the Department of Cell Biology and Molecular Medicine,*New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey; the Department of Neurology,{dagger}Molecular Neurobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; the Department of Medicine,{ddagger}Division of Clinical Pharmacology, New York University School of Medicine, New York, New York; and Merck and Company,§West Point, Pennsylvania

Under normoxic conditions, macrophages from C57BL mice produce low levels of vascular endothelial growth factor (VEGF). Hypoxia stimulates VEGF expression by ~500%; interferon-{gamma} (IFN-{gamma}) with endotoxin [lipopolysaccharide (LPS)] also stimulates VEGF expression by ~50 to 150% in an inducible nitric oxide synthase (iNOS)-dependent manner. Treatment of normoxic macrophages with 5'-N-ethyl-carboxamido-adenosine (NECA), a nonselective adenosine A2 receptor agonist, or with 2-[p-(2-carboxyethyl)-phenylethyl amino]-5'-N-ethyl-carboxamido-adenosine (CGS21680), a specific adenosine A2A receptor agonist, modestly increases VEGF expression, whereas 2-chloro-N6-cyclopentyl adenosine (CCPA), an adenosine A1 agonist, does not. Treatment with LPS (0 to 1000 ng/ml), or with IFN-{gamma} (0 to 300 U/ml), does not affect VEGF expression. In the presence of LPS (EC50 < 10 ng/ml), but not of IFN-{gamma}, both NECA and CGS21680 synergistically up-regulate VEGF expression by as much as 10-fold. This VEGF is biologically active in vivo in the rat corneal bioassay of angiogenesis. Inhibitors of iNOS do not affect this synergistic induction of VEGF, and macrophages from iNOS-/- mice produce similar levels of VEGF as wild-type mice, indicating that NO does not play a role in this induction. Under hypoxic conditions, VEGF expression is slightly increased by adenosine receptor agonists but adenosine A2 or A1 receptor antagonists 3,7-dimethyl-1-propargyl xanthine (DMPX), ZM241385, and 8-cyclopentyl-1,3-dipropylxanthine (DCPCX) do not modulate VEGF expression. VEGF expression is also not reduced in hypoxic macrophages from A3-/- and A2A-/- mice. Thus, VEGF expression by hypoxic macrophages does not seem to depend on endogenously released or exogenous adenosine. VEGF expression is strongly up-regulated by LPS/NECA in macrophages from A3-/- but not A2A-/- mice, confirming the role of adenosine A2A receptors in this pathway. LPS with NECA strongly up-regulates VEGF expression by macrophages from C3H/HeN mice (with intact Tlr4 receptors), but not by macrophages from C3H/HeJ mice (with mutated, functionally inactive Tlr4 receptors), implicating signaling through the Tlr4 pathway in this synergistic up-regulation. Finally, Western blot analysis of adenosine A2A receptor expression indicated that the synergistic interaction of LPS with A2A receptor agonists does not involve up-regulation of A2A receptors by LPS. These results indicate that in murine macrophages there is a novel pathway regulating VEGF production, that involves the synergistic interaction of adenosine A2A receptor agonists through A2A receptors with LPS through the Tlr4 pathway, resulting in the strong up-regulation of VEGF expression by macrophages in a hypoxia- and NO-independent manner.




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