title: Role of A2B adenosine receptors in regulation of paracrine functions of stem cell antigen 1-positive cardiac stromal cells.
abstract: The existence of multipotent cardiac stromal cells expressing stem cell antigen (Sca)-1 has been reported, and their proangiogenic properties have been demonstrated in myocardial infarction models. In this study, we tested the hypothesis that stimulation of adenosine receptors on cardiac Sca-1(+) cells up-regulates their secretion of proangiogenic factors. We found that Sca-1 is expressed in subsets of mouse cardiac stromal CD31(-) and endothelial CD31(+) cells. The population of Sca-1(+)CD31(+) endothelial cells was significantly reduced, whereas the population of Sca-1(+)CD31(-) stromal cells was increased 1 week after myocardial infarction, indicating their relative functional importance in this pathophysiological process. An increase in adenosine levels in adenosine deaminase-deficient mice in vivo significantly augmented vascular endothelial growth factor (VEGF) production in cardiac Sca-1(+)CD31(-) stromal cells but not in Sca-1(+)CD31(+) endothelial cells. We found that mouse cardiac Sca-1(+)CD31(-) stromal cells predominantly express mRNA encoding A(2B) adenosine receptors. Stimulation of adenosine receptors significantly increased interleukin (IL)-6, CXCL1 (a mouse ortholog of human IL-8), and VEGF release from these cells. Using conditionally immortalized Sca-1(+)CD31(-) stromal cells obtained from wild-type and A(2B) receptor knockout mouse hearts, we demonstrated that A(2B) receptors are essential for adenosine-dependent up-regulation of their paracrine functions. We found that the human heart also harbors a population of stromal cells similar to the mouse cardiac Sca-1(+)CD31(-) stromal cells that increase release of IL-6, IL-8, and VEGF in response to A(2B) receptor stimulation. Thus, our study identified A(2B) adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the ischemic heart.
authors.affiliation: Division of Cardiovascular Medicine, and Department of Medicine, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Ryzhov
authors.forename: Anna E
authors.initials: AE
authors.lastname: Goldstein
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
authors.forename: Igor
authors.initials: I
authors.lastname: Feoktistov
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000172:deficiency / Q000378:metabolism; D000361:Agammaglobulinemia / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D019899:Paracrine Communication / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000502:physiology*; D016511:Severe Combined Immunodeficiency / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D015850:Interleukin-6; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D043704:Receptor, Adenosine A2B; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000243:Adenosine Deaminase; D000241:Adenosine