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