Hypoxia Modulates Adenosine Receptors in Human Endothelial and Smooth Muscle Cells Toward an A <sub>2B</sub> Angiogenic Phenotype
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- Igor Feoktistov
- 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.
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- Sergey Ryzhov
- 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.
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- Hongyan Zhong
- 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.
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- Anna E. Goldstein
- 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.
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- Anton Matafonov
- 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.
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- Dewan Zeng
- 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.
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- 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.
抄録
<jats:p> We previously reported that adenosine A <jats:sub>2B</jats:sub> 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 <jats:sub>2A</jats:sub> phenotype (the selective A <jats:sub>2A</jats:sub> agonist CGS21680 was as potent as the nonselective agonist 5′- <jats:italic>N</jats:italic> -ethylcarboxamidoadenosine [NECA] in generating cAMP). Hypoxia (4.6% O <jats:sub>2</jats:sub> , 3 hours) decreased A <jats:sub>2A</jats:sub> mRNA from 1.56±0.3% to 0.16±0.01% of β-actin expression but increased A <jats:sub>2B</jats:sub> 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 <jats:sub>2B</jats:sub> phenotype), and NECA increased VEGF release from 9.5±1.0 to 14.2±1.2 pg/mL ( <jats:italic>P</jats:italic> <0.05), indicating that increased A <jats:sub>2B</jats:sub> receptors were functionally coupled to upregulation of VEGF. Hypoxia had similar effects on BSMCs, increasing A <jats:sub>2B</jats:sub> mRNA by 2.4±0.3-fold, from 0.42±0.04% to 1.00±0.13% of β-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 ( <jats:italic>P</jats:italic> <0.01), and a selective A <jats:sub>2B</jats:sub> antagonist, CVT-6694, inhibited this increase. A <jats:sub>2B</jats:sub> 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 <jats:sub>2B</jats:sub> “angiogenic” phenotype. </jats:p>
収録刊行物
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- Hypertension
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Hypertension 44 (5), 649-654, 2004-11
Ovid Technologies (Wolters Kluwer Health)