Circulation Research. 2002
Published online before print January 31, 2002, doi: 10.1161/01.RES.0000012203.21416.14
Published online before print January 31, 2002, doi: 10.1161/01.RES.0000012203.21416.14
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Submitted on December 12, 2001
Revised on January 22, 2002
Accepted on January 22, 2002
Differential Expression of Adenosine Receptors in Human Endothelial Cells. Role of A2B Receptors in Angiogenic Factor Regulation
Igor Feoktistov *;
From the Divisions of Cardiology (I.F., A.E.G.) and Clinical Pharmacology (S.R., I.B.), Departments of Medicine (I.F., A.E.G., S.R., I.B.) and Pharmacology (I.F., I.B.), Vanderbilt University, Nashville, Tenn; CV Therapeutics (D.Z., L.B.), Palo Alto, Calif; and the Department of Pharmacology (T.V.-Y.), University of Illinois, Chicago, Ill.
* To whom correspondence should be addressed. E-mail: igor.feoktistov{at}mcmail.vanderbilt.edu.
Adenosine has been reported to stimulate or inhibit the release of angiogenic factors depending on the cell type examined. To test the hypothesis that differential expression of adenosine receptor subtypes contributes to endothelial cell heterogeneity, we studied microvascular (HMEC-1) and umbilical vein (HUVEC) human endothelial cells. Based on mRNA level and stimulation of adenylate cyclase, we found that HUVECs preferentially express A2A adenosine receptors and HMEC-1 preferentially express A2B receptors. Neither cells expressed A1 or A3 receptors. The nonselective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased expression of interleukin-8 (IL-8), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in HMEC-1, but had no effect in HUVECs. In contrast, the selective A2A agonist 2-p-(2-carboxyethyl)phenethylamino-NECA (CGS 21680) had no effect on expression of these angiogenic factors. Cotransfection of each type of adenosine receptors with a luciferase reporter in HMEC-1 showed that A2B receptors, but not A1, A2A, or A3, activated IL-8 and VEGF promoters. These effects were mimicked by constitutively active 
Gq, G12, and G13, but not Gs or Gi1-3. Furthermore, stimulation of phospholipase C indicated coupling of A2B receptors to Gq proteins in HMEC-1. Thus, differential expression of adenosine receptor subtypes contributes to functional heterogeneity of human endothelial cells. A2B receptors, predominantly expressed in human microvascular cells, modulate expression of angiogenic factors via coupling to Gq, and possibly via G12/13.
Key words: adenosine receptors • vascular endothelium • angiogenesis • vascular endothelial growth factor • interleukin-8
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