on September 27, 2004
Published online before print September 27, 2004, doi: 10.1161/01.HYP.0000144800.21037.a5
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Submitted on April 9, 2004
From the Divisions of Cardiovascular Medicine (I.F., A.E.G.) and Clinical Pharmacology (S.R., A.M., I.B.) and the Departments of Medicine (I.F., A.E.G., I.B.) and Pharmacology (S.R., A.M., I.B.), Vanderbilt University, Nashville, Tenn; and the Department of Drug Research and Pharmacological Sciences (H.Z., D.Z.), CV Therapeutics, Inc, Palo Alto, Calif. * To whom correspondence should be addressed. E-mail: igor.feoktistov{at}vanderbilt.edu.
Abstract--We previously reported that adenosine A2B receptor activation stimulates angiogenesis. Because hypoxia is a potent stimulus for the release of both adenosine and angiogenic factors, we tested the hypothesis that hypoxia alters the expression of adenosine receptors toward an "angiogenic" phenotype. We used human umbilical vein endothelial cells (HUVECs) and bronchial smooth muscle cells (BSMCs) because, under normoxic conditions, adenosine does not release vascular endothelial growth factor (VEGF). HUVECs expressed a characteristic A2A phenotype (the selective A2A agonist CGS21680 was as potent as the nonselective agonist 5'-N-ethylcarboxamidoadenosine [NECA] in generating cAMP). Hypoxia (4.6% O2, 3 hours) decreased A2A mRNA from 1.56±0.3% to 0.16±0.01% of
Revised on April 28, 2004
Hypoxia Modulates Adenosine Receptors in Human Endothelial and Smooth Muscle Cells Toward an A2B Angiogenic Phenotype
Igor Feoktistov*;
-actin expression but increased A2B mRNA from 0.08±0.01% to 0.27±0.05%. Consistent with changes in receptor expression, CGS21680 failed to increase cAMP in hypoxic HUVECs, whereas NECA remained active (A2B phenotype), and NECA increased VEGF release from 9.5±1.0 to 14.2±1.2 pg/mL (P<0.05), indicating that increased A2B receptors were functionally coupled to upregulation of VEGF. Hypoxia had similar effects on BSMCs, increasing A2B mRNA by 2.4±0.3-fold, from 0.42±0.04% to 1.00±0.13% of -actin. Whereas NECA had no effect on VEGF release in normoxic BSMCs, it increased VEGF release in hypoxic BSMCs, from 74.6±9.6 to 188.3±16.7 pg/mL (P<0.01), and a selective A2B antagonist, CVT-6694, inhibited this increase. A2B receptors activated a VEGF reporter made unresponsive to hypoxia by mutating its hypoxia-inducible factor-1 (HIF-1) binding element, indicating a mechanism independent of HIF-1. In conclusion, hypoxia modulates the expression of adenosine receptors in human endothelial and smooth muscle cells toward an A2B"angiogenic" phenotype.
Key words: adenosine • hypoxia • receptors, purinergic • endothelium • vasculature • muscle, smooth • endothelium-derived factors
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