Journal
HYPERTENSION
Volume 44, Issue 5, Pages 649-654Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.HYP.0000144800.21037.a5
Keywords
adenosine; hypoxia; receptors, purinergic; endothelium; vasculature; muscle, smooth; endothelium-derived factors
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Funding
- NHLBI NIH HHS [R01 HL67232, R01 HL70073] Funding Source: Medline
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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 ( EGF). 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% O-2, 3 hours) decreased A(2A) mRNA from 1.56 +/- 0.3% to 0.16 +/- 0.01% of beta-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 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 (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.
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