The Essential Role of Angiogenesis in Adenosine 2A Receptor Deficiency-mediated Impairment of Wound Healing Involving c-Ski via the ERK/CREB Pathways.

Adenosine receptor-mediated signaling, especially adenosine A receptor (AR) signaling, has been implicated in wound healing. However, the role of endothelial cells (ECs) in AR-mediated wound healing and the mechanism underlying this effect are still unclear. Here, we showed that the expression of AR substantially increased after wounding and was especially prominent in granulation tissue. The delaying effects of AR knockout (KO) on wound healing are due mainly to the effect of AR on endothelial cells, as shown with AR-KO and EC-AR-KO mice. Moreover, the expression of c-Ski, which is especially prominent in CD31-positive cells in granulation tissue, increased after wounding and was decreased by both EC-AR KO and AR KO. In human microvascular ECs (HMECs), AR activation induced EC proliferation, migration, tubule formation and c-Ski expression, whereas c-Ski depletion by RNAi abolished these effects. Mechanistically, AR activation promotes the expression of c-Ski through an ERK/CREB-dependent pathway. Thus, AR-mediated angiogenesis plays a critical role in wound healing, and c-Ski is involved mainly in the regulation of angiogenesis by AR via the ERK/CREB pathway. These findings identify AR as a therapeutic target in wound repair and other angiogenesis-dependent tissue repair processes.