P2Y(2)R activation by nucleotides promotes skin wound-healing process

Abstract

P2Y(2)R has been shown to be upregulated in a variety of tissues in response to stress or injury and to mediate tissue regeneration through its ability to activate multiple signalling pathways. This study aimed to investigate the role of P2Y(2)R in the wound-healing process and the mechanisms by which P2Y(2)R activation promotes wound healing in fibroblasts. The role of P2Y(2)R in skin wound healing was examined using a full-thickness skin wound model in wildtype (WT) and P2Y(2)R(-/-) mice and an in vitro scratch wound model in control or P2Y(2)R siRNA-transfected fibroblasts. WT mice showed significantly decreased wound size compared with P2Y(2)R(-/-) mice at day 14 postwounding, and immunohistochemical analysis showed that a proliferation marker Ki67 and extracellular matrix (ECM)-related proteins VEGF, collagen I, fibronectin and alpha-SMA were overexpressed in WT mice, which were reduced in P2Y(2)R(-/-) mice. Scratch-wounded fibroblasts increased ATP release, which peaked at 5 min. In addition, scratch wounding increased the level of P2Y(2)R mRNA. Activation of P2Y(2)R by ATP or UTP enhanced proliferation and migration of fibroblasts in in vitro scratch wound assays and were blocked by P2Y(2)R siRNA. Finally, ATP or UTP also increased the levels of ECM-related proteins through the activation of P2Y(2)R in fibroblasts. This study suggests that P2Y(2)R may be a potential therapeutic target to promote wound healing in chronic wound diseases.