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.