MEK/ERK/1/2 sensitive vascular changes coincide with retinal functional deficit, following transient ophthalmic artery occlusion. (February 2019)

• Record Type: Journal Article
• Authors: Blixt, Frank W.; Haanes, Kristian Agmund; Ohlsson, Lena; Dreisig, Karin; Fedulov, Vadim; Warfvinge, Karin; Edvinsson, Lars
• Is Part Of: Experimental eye research. Volume 179(2019)
• Page Start: 142
• Page End: 149
• Publication Date: 2019-02
• Subjects: Retinal ischemia -- Endothelin-1 -- Ophthalmic artery -- Vascular changes -- mek/erk1/2; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2018.11.003
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Retinal ischemia remains a major cause of blindness in the world with few acute treatments available. Recent emphasis on retinal vasculature and the ophthalmic artery's vascular properties after ischemia has shown an increase in vasoconstrictive functionality, as previously observed in cerebral arteries following stroke. Specifically, endothelin-1 (ET-1) receptor-mediated vasoconstriction regulated by the MEK/ERK1/2 pathway. In this study, the ophthalmic artery of rats was occluded for 2 h with the middle cerebral artery occlusion model. MEK/ERK1/2 inhibitor U0126 was administered at 0, 6, and 24 h following reperfusion and the functional properties of the ophthalmic artery were evaluated at 48 h post reperfusion. Additionally, retinal function was evaluated at day 1, 4, and 7 after reperfusion. Occlusion of the ophthalmic artery led to a significant increase of endothelin-1 mediated vasoconstriction which can be attenuated by U0126 treatment, most evident at higher ET-1 concentrations of 10 −7 M (Emax 151.0 ± 22.0% of 60 mM K + ), vs non-treated ischemic arteries Emax 212.1 ± 14.7% of 60 mM K + ). Retinal function also deteriorated following ischemia and was improved with treatment with a-wave amplitudes of 725 ± 36 μV in control, 560 ± 21 μV in non-treated, and 668 ± 73 μV in U0126 treated at 2 log cd*s/m 2 luminance in the acute stages (1 days post-ischemia). Full spontaneous retinal recovery was observed at day 7 regardless of treatment. In conclusion, this is the first study to show a beneficial in vivo effect of U0126 on vascular contractility following ischemia in the ophthalmic artery. Coupled with the knowledge obtained from cerebral vasculature, these results point towards a novel therapeutic approach following ischemia-related injuries to the eye. Highlights: 2 h ophthalmic artery occlusion via the middle cerebral artery occlusion model. Increased Endothelin-1 mediated vasoconstriction observed in occluded eye, but not in control. MEK/ERK1/2 inhibitor U0126 inhibits increased Endothelin-1 mediated vasoconstriction following occlusion. U0126 accelerates spontaneous retinal function which is achieved at day 7.