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_2A receptor (A_2AR) signaling, has been implicated in wound healing. However, the role of endothelial cells (ECs) in A_2AR-mediated wound healing and the mechanism underlying this effect are still unclear. Here, we showed that the expression of A_2AR substantially increased after wounding and was especially prominent in granulation tissue. The delaying effects of A_2AR knockout (KO) on wound healing are due mainly to the effect of A_2AR on endothelial cells, as shown with A_2AR-KO and EC-A_2AR-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_2AR KO and A_2AR KO. In human microvascular ECs (HMECs), A_2AR activation induced EC proliferation, migration, tubule formation and c-Ski expression, whereas c-Ski depletion by RNAi abolished these effects. Mechanistically, A_2AR activation promotes the expression of c-Ski through an ERK/CREB-dependent pathway. Thus, A_2AR-mediated angiogenesis plays a critical role in wound healing, and c-Ski is involved mainly in the regulation of angiogenesis by A_2AR via the ERK/CREB pathway. These findings identify A_2AR as a therapeutic target in wound repair and other angiogenesis-dependent tissue repair processes.