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MEK/ERK/1/2 sensitive vascular changes coincide with retinal functional deficit, following transient ophthalmic artery occlusion

Blixt, Frank W. LU ; Haanes, Kristian Agmund; Ohlsson, Lena LU ; Dreisig, Karin; Fedulov, Vadim; Warfvinge, Karin LU and Edvinsson, Lars LU (2019) In Experimental Eye Research 179. p.142-149
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... (More)

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 (Emax151.0 ± 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/m2 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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Endothelin-1, mek/erk1/2, Ophthalmic artery, Retinal ischemia, Vascular changes
in
Experimental Eye Research
volume
179
pages
8 pages
publisher
Elsevier
external identifiers
  • scopus:85056887470
ISSN
0014-4835
DOI
10.1016/j.exer.2018.11.003
language
English
LU publication?
yes
id
dd1b6051-f7f8-4a51-af86-23b43ef1f06d
date added to LUP
2018-11-29 10:29:53
date last changed
2019-01-06 14:17:52
@article{dd1b6051-f7f8-4a51-af86-23b43ef1f06d,
  abstract     = {<p>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<sup>−7</sup> M (E<sub>max</sub>151.0 ± 22.0% of 60 mM K<sup>+</sup>), vs non-treated ischemic arteries E<sub>max</sub> 212.1 ± 14.7% of 60 mM K<sup>+</sup>). 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<sup>2</sup> 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.</p>},
  author       = {Blixt, Frank W. and Haanes, Kristian Agmund and Ohlsson, Lena and Dreisig, Karin and Fedulov, Vadim and Warfvinge, Karin and Edvinsson, Lars},
  issn         = {0014-4835},
  keyword      = {Endothelin-1,mek/erk1/2,Ophthalmic artery,Retinal ischemia,Vascular changes},
  language     = {eng},
  pages        = {142--149},
  publisher    = {Elsevier},
  series       = {Experimental Eye Research},
  title        = {MEK/ERK/1/2 sensitive vascular changes coincide with retinal functional deficit, following transient ophthalmic artery occlusion},
  url          = {http://dx.doi.org/10.1016/j.exer.2018.11.003},
  volume       = {179},
  year         = {2019},
}