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(Hypertension. 2004;44:649.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Hypoxia Modulates Adenosine Receptors in Human Endothelial and Smooth Muscle Cells Toward an A_2B Angiogenic Phenotype

Igor Feoktistov; Sergey Ryzhov; Hongyan Zhong; Anna E. Goldstein; Anton Matafonov; Dewan Zeng; Italo Biaggioni

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.

Correspondence to Igor Feoktistov, PhD, 360 PRB, Vanderbilt University, Nashville, TN 37232-6300. E-mail igor.feoktistov{at}vanderbilt.edu

We previously reported that adenosine A_2B 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 A_2A phenotype (the selective A_2A agonist CGS21680 was as potent as the nonselective agonist 5'-N-ethylcarboxamidoadenosine [NECA] in generating cAMP). Hypoxia (4.6% O₂, 3 hours) decreased A_2A mRNA from 1.56±0.3% to 0.16±0.01% of ß-actin expression but increased A_2B 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 (A_2B phenotype), and NECA increased VEGF release from 9.5±1.0 to 14.2±1.2 pg/mL (P<0.05), indicating that increased A_2B receptors were functionally coupled to upregulation of VEGF. Hypoxia had similar effects on BSMCs, increasing A_2B mRNA by 2.4±0.3-fold, from 0.42±0.04% to 1.00±0.13% of ß-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 A_2B antagonist, CVT-6694, inhibited this increase. A_2B 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 A_2B"angiogenic" phenotype.

Key Words: adenosine • hypoxia • receptors, purinergic • endothelium • vasculature • muscle, smooth • endothelium-derived factors

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