An agonist of the adenosine A2A receptor, CGS21680, promotes corneal epithelial wound healing via the YAP signalling pathway

Abstract

AbstractBackground and PurposeThe adenosine A2A receptor (A2AR) is involved in various physiological and pathological processes in the eye; however, the role of the A2AR signalling in corneal epithelial wound healing is not known. Here, the expression, therapeutic effects and signalling mechanism of A2AR in corneal epithelial wound healing were investigated using the A2AR agonist CGS21680.Experimental ApproachA2AR localization and expression during wound healing in the murine cornea were determined by immunofluorescence staining, quantitative reverse transcription polymerase chain reaction (RT‐qPCR) and western blotting. The effect of CGS21680 on corneal epithelial wound healing in the lesioned corneal and cultured human corneal epithelial cells (hCECs) by modulating cellular proliferation and migration was critically evaluated. The role of Hippo–YAP signalling in mediating the CGS21680 effect on wound healing by pharmacological inhibition of YAP signalling was explored.Key ResultsA2AR expression was up‐regulated after corneal epithelial injury. Topical administration of CGS21680 dose‐dependently promoted corneal epithelial wound healing in the injured corneal epithelium by promoting cellular proliferation. Furthermore, CGS21680 accelerated the cellular proliferation and migration of hCECs in vitro. A2AR activation promoted early up‐regulation and later down‐regulation of YAP signalling molecules, and pharmacological inhibition of YAP signalling reverted CGS21680‐mediated wound healing effect in vivo and in vitro.Conclusion and ImplicationsA2AR activation promotes wound healing by enhancing cellular proliferation and migration through the YAP signalling pathway. A2ARs play an important role in the maintenance of corneal epithelium integrity and may represent a novel therapeutic target for facilitating corneal epithelial wound healing.