A2B Adenosine Receptors Stimulate Release of IL‐6, CXCL1/IL‐8 and Vascular Growth Factor from Cardiac Stromal Cells

Abstract

Proangiogenic properties of cardiac stromal cells expressing stem cell antigen (Sca)‐1 were demonstrated in myocardial infarction models. Interstitial adenosine, known to be increased in ischemic tissues, has been suggested to promote angiogenesis. In this study, we tested the hypothesis that stimulation of adenosine receptors on cardiac stromal cells promotes secretion of proangiogenic factors. Using magnetic sorting, we isolated mouse cardiac Sca‐1+CD31− stromal cells. We determined that they predominantly express mRNA encoding the A2B adenosine receptor subtype and low levels of A2A adenosine receptor transcripts. Stimulation of adenosine receptors with 5′‐N‐ethylcarboxamidoadenosine (NECA) increased IL‐6, CXCL1 and vascular growth factor (VEGF) release by 2–4‐fold. Using conditionally immortalized Sca‐1+CD31− stromal cells obtained from wild‐type and A2B receptor knockout mouse hearts, we demonstrated that the A2B receptor subtype is essential for adenosine‐dependent upregulation of their paracrine functions. We found that the human heart also harbors a similar population of stromal cells that predominantly express A2B receptors and respond to stimulation with by increased IL‐6, IL‐8 and VEGF release. Thus, our study identified A2B adenosine receptors on cardiac stromal cells as potential targets for upregulation of proangiogenic factors in the ischemic heart. Support: R01HL095787