Abstract
Purpose :
Retinal ischemic injury is involved in numerous ocular diseases. cAMP is the first identified second messenger and is prevalent in many pathophysiological processes. In addition to its main effector PKA, cAMP influences cellular function via exchange protein directly activated by cAMP (Epac). We have previously shown that neuronal Epac1 is a key regulator in retinal neurodegeneration. Epac2, the other isoform of Epac, is also abundant in retina. This study aims to investigate whether Epac2 has a role in retinal neurovascular degeneration in a mouse model of retinal ischemia-reperfusion (IR).
Methods :
IR was induced by elevating intraocular pressure to 110 mm Hg for 50 minutes. Epac2 mRNA was examined by in situ hybridization. Neuronal apoptosis, retinal ganglion cell (RGC) loss and axonal degeneration in the optic nerve were determined by TUNEL assay and immunohistochemistry. Leukocyte adhesion was assessed by leukostasis assay. Subjective and objective visual functions were evaluated by visual acuity and pattern electroretinogram (PERG) respectively. The alterations of retinal vasculature were identified by optical coherence tomography angiography (OCTA) and further confirmed by immunostaining.
Results :
At 12 hours after IR, a drastic increase of Epac2 mRNA was observed in the retina of WT mice. Neuronal apoptosis was dramatically increased in WT IR retinas, which were significantly mitigated by Epac2 genetic deletion. Leukostasis assay revealed fewer adherent leukocytes in Epac2-/- mice. RGC number, axons in the optic nerve and visual functions were significantly preserved in Epac2-/- mice at 1 week or 3 weeks after IR. OCTA and isolectin B4 staining demonstrated notable decreases in vessel density, number of junctions and total vessel length in both intermediate and deep capillary plexus of WT IR retinas, whereas Epac2 deletion significantly alleviated these changes.
Conclusions :
These data indicate that Epac2 deletion is neurovascular protective against retinal IR injury and Epac2 blockade may be a promising strategy in the treatment of retinal neurodegenerative diseases.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.