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.