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Am J Physiol Heart Circ Physiol 277: H595-H602, 1999;
0363-6135/99 $5.00
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Vol. 277, Issue 2, H595-H602, August 1999

Adenosine upregulates VEGF expression in cultured myocardial vascular smooth muscle cells

Jian-Wei Gu, Ann L. Brady, Vivek Anand, Michael C. Moore, Whitney C. Kelly, and Thomas H. Adair

Department of Physiology and Biophysics, and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505

We tested whether adenosine has differential effects on vascular endothelial growth factor (VEGF) expression under normoxic and hypoxic conditions, and whether A1 or A2 receptors (A1R; A2R) mediate these effects. Myocardial vascular smooth muscle cells (MVSMCs) from dog coronary artery were exposed to hypoxia (1% O2) or normoxia (20% O2) in the absence and presence of adenosine agonists or antagonists for 18 h. VEGF protein levels were measured in media with ELISA. VEGF mRNA expression was determined with Northern blot analysis. Under normoxic conditions, the adenosine A1R agonists, N6-cyclopentyladenosine and R(-)-N6-(2-phenylisopropyl)adenosine did not increase VEGF protein levels at A1R stimulatory concentrations. However, adenosine (5 µM) and the adenosine A2R agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]ethyl adenosine (DPMA; 100 nM) increased VEGF protein levels by 51 and 132% and increased VEGF mRNA expression by 44 and 90%, respectively, in cultured MVSMCs under normoxic conditions. Hypoxia caused an approximately fourfold increase in VEGF protein and mRNA expression, which could not be augmented with exogenous adenosine, A2R agonist (DPMA), or A1R agonist [1,3-diethyl-8-phenylxanthine (DPX)]. The A2R antagonist 8-(3-chlorostyryl)-caffeine completely blocked adenosine-induced VEGF protein and mRNA expression and decreased baseline VEGF protein levels by up to ~60% under normoxic conditions but only by ~25% under hypoxic conditions. The A1R antagonist DPX had no effect. These results are consistent with the hypothesis that 1) adenosine increases VEGF protein and mRNA expression by way of A2R. 2) Adenosine plays a major role as an autocrine factor regulating VEGF expression during normoxic conditions but has a relatively minor role during hypoxic conditions. 3) Endogenous adenosine can account for the majority of basal VEGF secretion by MVSMCs under normoxic conditions and could therefore be a maintenance factor for the vasculature.

vascular endothelial growth factor; hypoxia; normoxia; vascular smooth muscle cells; adenosine receptor; vascular maintenance factor


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