© 1999 American Heart Association, Inc.
Cellular Biology |
Adenosine Receptor Activation Induces Vascular Endothelial Growth Factor in Human Retinal Endothelial Cells
From the Departments of Medicine (M.B.G., R.W.T., S.C., M.I.D., P.E.S., J.C.S., L.B.), Ophthalmology (M.B.G.), and Pharmacology and Therapeutics (M.J.O., J.C.S., L.B.), University of Florida, Gainesville, Fla, and Department of Medicine and Pharmacology (I.F., I.B.), Vanderbilt University, Nashville, Tenn. L.B.'s current address is Pharmacological Sciences, CV Therapeutics, Palo Alto, Calif.
Correspondence to M.B. Grant, MD, Associate Professor of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of Florida, P.O. Box 100226, Gainesville, FL 32610-0226. E-mail grantma{at}medicine.ufl.edu
Abstract—Adenosine, released in increased amounts by hypoxic tissues, is thought to be an angiogenic factor that links altered cellular metabolism caused by oxygen deprivation to compensatory angiogenesis. Adenosine interacts with 4 subtypes of G protein–coupled receptors, termed A1, A2A, A2B, and A3. We investigated whether adenosine causes proliferation of human retinal endothelial cells (HRECs) and synthesis of vascular endothelial growth factor (VEGF) and, if so, which adenosine receptor subtype mediates these effects. The nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), in a concentration-dependent manner, increased both VEGF mRNA and protein expression by HRECs, as well as proliferation. This proliferative effect of NECA was inhibited by the addition of anti-human VEGF antibody. NECA also increased insulin-like growth factor-I and basic fibroblast growth factor mRNA expression in a time-dependent manner and cAMP accumulation in these cells. In contrast, neither the A1 agonist N6-cyclopentyladenosine nor the A2A agonist 2-p-(2-carboxyethyl) phenethylamino-NECA caused any of the above effects of NECA. The effects of NECA were not significantly attenuated by either the A2A antagonist SCH58261 or the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine. However, the nonselective adenosine receptor antagonist xanthine amine congener completely inhibited the effects of NECA. Addition of antisense oligonucleotide complementary to A2B adenosine receptor mRNA inhibited VEGF protein production by HRECs after NECA stimulation. Thus, the A2B adenosine receptor subtype appears to mediate the actions of adenosine to increase growth factor production, cAMP content, and cell proliferation of HRECs. Adenosine activates the A2B adenosine receptor in HRECs, which may lead to neovascularization by a mechanism involving increased angiogenic growth factor expression.
Key Words: adenosine receptor • angiogenesis • ischemia • hypoxia • diabetes
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