PMID- 15452028
OWN - NLM
STAT- MEDLINE
DCOM- 20050421
LR  - 20160726
IS  - 1524-4563 (Electronic)
IS  - 0194-911X (Linking)
VI  - 44
IP  - 5
DP  - 2004 Nov
TI  - Hypoxia modulates adenosine receptors in human endothelial and smooth muscle 
      cells toward an A2B angiogenic phenotype.
PG  - 649-54
AB  - 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 beta-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 beta-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.
FAU - Feoktistov, Igor
AU  - Feoktistov I
AD  - Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN 
      37232-6300, USA. igor.feoktistov@vanderbilt.edu
FAU - Ryzhov, Sergey
AU  - Ryzhov S
FAU - Zhong, Hongyan
AU  - Zhong H
FAU - Goldstein, Anna E
AU  - Goldstein AE
FAU - Matafonov, Anton
AU  - Matafonov A
FAU - Zeng, Dewan
AU  - Zeng D
FAU - Biaggioni, Italo
AU  - Biaggioni I
LA  - eng
GR  - R01 HL67232/HL/NHLBI NIH HHS/United States
GR  - R01 HL70073/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040927
PL  - United States
TA  - Hypertension
JT  - Hypertension (Dallas, Tex. : 1979)
JID - 7906255
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptor, Adenosine A2B)
RN  - 0 (Receptors, Purinergic P1)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
CIN - Hypertension. 2004 Nov;44(5):618-20. PMID: 15381681
MH  - Cell Hypoxia/*physiology
MH  - Cells, Cultured
MH  - DNA-Binding Proteins/physiology
MH  - Down-Regulation
MH  - Endothelial Cells/*metabolism
MH  - Gene Expression
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Myocytes, Smooth Muscle/*metabolism
MH  - *Neovascularization, Physiologic
MH  - Nuclear Proteins/physiology
MH  - Phenotype
MH  - RNA, Messenger
MH  - Receptor, Adenosine A2B/physiology
MH  - Receptors, Purinergic P1/*physiology
MH  - Transcription Factors/physiology
MH  - Vascular Endothelial Growth Factor A/*metabolism
EDAT- 2004/09/29 05:00
MHDA- 2005/04/22 09:00
CRDT- 2004/09/29 05:00
PHST- 2004/09/29 05:00 [pubmed]
PHST- 2005/04/22 09:00 [medline]
PHST- 2004/09/29 05:00 [entrez]
AID - 01.HYP.0000144800.21037.a5 [pii]
AID - 10.1161/01.HYP.0000144800.21037.a5 [doi]
PST - ppublish
SO  - Hypertension. 2004 Nov;44(5):649-54. doi: 10.1161/01.HYP.0000144800.21037.a5. 
      Epub 2004 Sep 27.