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

  • Br J Pharmacol. 2020 Aug;177(15):3389-3402. doi: 10.1111/bph.15059.
Ruyi Zhai  1  2  3  4 ,  Huan Xu  1  2  3  4 ,  Fangyuan Hu  2  3  4 ,  Jihong Wu  1  2  3  4 ,  Xiangmei Kong  1  2  3  4 ,  Xinghuai Sun  1  2  3  4  5
Affiliations
  • 1. Department of Ophthalmology and Visual Science, Eye, Ear, Nose and Throat Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
  • 2. Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China.
  • 3. NHC Key Laboratory of Myopia, Fudan University, Shanghai, China.
  • 4. Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.
  • 5. State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China.
PMID: 32232832 DOI: 10.1111/bph.15059
Abstract

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.

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