Exendin‐4, a GLP‐1 receptor agonist regulates retinal capillary tone and restores microvascular patency after ischaemia–reperfusion injury

BACKGROUND AND PURPOSE: The aim of this study is to investigate the vasorelaxant effect of exendin‐4, a GLP‐1 receptor agonist on retinal capillaries under normal and ischaemia–reperfusion (I/R) conditions. EXPERIMENTAL APPROACH: Capillary diameters in the whole‐mounted retina were directly observed using infrared differential interference contrast microscopy. A model of retinal I/R was established inraats,using high perfusion pressure in an anterior chamber. To assess the effects of exendin‐4, it was administered through subcutaneous injection, intravitreal injection, or eye drops. The underlying mechanism was explored by immunofluorescence, qPCR, and capillary western blots. KEY RESULTS: Immunofluorescence staining showed that GLP‐1 receptors were expressed in endothelial cells of retinal capillaries. Exendin‐4 relaxed the capillaries precontracted by noradrenaline, an effect abolished by denuding endothelium with CHAPS and inhibited by GLP‐1 receptor antagonist exendin‐9‐39, endothelial NOS (eNOS) inhibitor l‐NAME, and the guanylate cyclase blocker ODQ but not by a COX inhibitor, indomethacin. Retinal capillaries were constricted in I/R injury, an effect reversed by perfusion of exendin‐4. Expression of PI3K and Akt, phosphorylation level of eNOS and NO production after I/R were lower than that in the normal control group. Administration of exendin‐4 improved the changes. CONCLUSION AND IMPLICATIONS: Exendin‐4 can restore injured microvascular patency in I/R. Exendin‐4 may regulate retinal capillaries through the GLP‐1 receptor‐PI3K/Akt‐eNOS/NO‐cGMP pathway. Therefore, exendin‐4 may be an effective treatment for improving tissue perfusion in I/R‐related conditions.