TY - JOUR T1 - Role of A<sub>2B</sub> Adenosine Receptors in Regulation of Paracrine Functions of Stem Cell Antigen 1-Positive Cardiac Stromal Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 764 LP - 774 DO - 10.1124/jpet.111.190835 VL - 341 IS - 3 AU - Sergey Ryzhov AU - Anna E. Goldstein AU - Sergey V. Novitskiy AU - Michael R. Blackburn AU - Italo Biaggioni AU - Igor Feoktistov Y1 - 2012/06/01 UR - http://jpet.aspetjournals.org/content/341/3/764.abstract N2 - 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 A2B 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 A2B receptor knockout mouse hearts, we demonstrated that A2B 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 A2B receptor stimulation. Thus, our study identified A2B adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the ischemic heart. ER -