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Increased endothelin-1-mediated vasoconstriction after organ culture in rat and pig ocular arteries can be suppressed with MEK/ERK1/2 inhibitors

W Blixt, Frank LU ; Kristian Haanes, Agmund ; Ohlsson, Lena LU ; Tolstrup Christiansen, Anders ; Warfvinge, Karin LU orcid and Edvinsson, Lars LU (2018) In Acta Ophthalmologica 96(5). p.619-625
Abstract

PURPOSE: Even though retinal vascular changes following ischaemia have been poorly understood, the upregulation of vasoconstrictive endothelin-1 (ET-1) receptors (ETA/ETB) following global cerebral ischaemia has been described. The aim of this study was to investigate whether or not the MEK/ERK1/2 pathway is involved in the observed upregulation and whether specific MEK/ERK1/2 inhibitors U0126 and trametinib can prevent it.

METHODS: The aim was also to localize ETAand ETBreceptors using immunohistochemistry in both fresh rat ophthalmic arteries and after 24-hr organ culture and study the receptors functionally using myography. Pig retinal arteries also underwent 24-hr organ culture to validate similar responses across species and... (More)

PURPOSE: Even though retinal vascular changes following ischaemia have been poorly understood, the upregulation of vasoconstrictive endothelin-1 (ET-1) receptors (ETA/ETB) following global cerebral ischaemia has been described. The aim of this study was to investigate whether or not the MEK/ERK1/2 pathway is involved in the observed upregulation and whether specific MEK/ERK1/2 inhibitors U0126 and trametinib can prevent it.

METHODS: The aim was also to localize ETAand ETBreceptors using immunohistochemistry in both fresh rat ophthalmic arteries and after 24-hr organ culture and study the receptors functionally using myography. Pig retinal arteries also underwent 24-hr organ culture to validate similar responses across species and the retinal vasculature.

RESULTS: Results showed that following organ culture there is a significant increase in ET-1-mediated vasoconstriction, in particular via the ETBreceptor. Furthermore, immunohistochemistry revealed a clear increase in pERK in the smooth muscle cells of rat ophthalmic artery. U0126 and trametinib were successful in attenuating the functional vasoconstriction in both rat and pig, as well as restoring immunofluorescence of pERK to fresh levels and counteracting ETBexpression in the smooth muscle cells of the rat ophthalmic artery.

CONCLUSION: This is the first study to show that the MEK/ERK1/2 pathway in responsible for the increase in functional vasoconstriction via ET-1 receptor in rat ophthalmic and pig retinal arteries. Furthermore, this study is the first to suggest a way of inhibiting and preventing such an increase. With these results, we suggest a novel approach in retinal ischaemia therapy.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Journal Article
in
Acta Ophthalmologica
volume
96
issue
5
pages
619 - 625
publisher
Wiley-Blackwell
external identifiers
  • scopus:85041058521
  • pmid:29369532
ISSN
1755-3768
DOI
10.1111/aos.13651
language
English
LU publication?
yes
id
36f7a89d-ff53-4b14-a5e2-6627fdf5cf5e
date added to LUP
2018-02-16 13:57:03
date last changed
2021-10-06 03:34:24
@article{36f7a89d-ff53-4b14-a5e2-6627fdf5cf5e,
  abstract     = {<p>PURPOSE: Even though retinal vascular changes following ischaemia have been poorly understood, the upregulation of vasoconstrictive endothelin-1 (ET-1) receptors (ETA/ETB) following global cerebral ischaemia has been described. The aim of this study was to investigate whether or not the MEK/ERK1/2 pathway is involved in the observed upregulation and whether specific MEK/ERK1/2 inhibitors U0126 and trametinib can prevent it.</p><p>METHODS: The aim was also to localize ETAand ETBreceptors using immunohistochemistry in both fresh rat ophthalmic arteries and after 24-hr organ culture and study the receptors functionally using myography. Pig retinal arteries also underwent 24-hr organ culture to validate similar responses across species and the retinal vasculature.</p><p>RESULTS: Results showed that following organ culture there is a significant increase in ET-1-mediated vasoconstriction, in particular via the ETBreceptor. Furthermore, immunohistochemistry revealed a clear increase in pERK in the smooth muscle cells of rat ophthalmic artery. U0126 and trametinib were successful in attenuating the functional vasoconstriction in both rat and pig, as well as restoring immunofluorescence of pERK to fresh levels and counteracting ETBexpression in the smooth muscle cells of the rat ophthalmic artery.</p><p>CONCLUSION: This is the first study to show that the MEK/ERK1/2 pathway in responsible for the increase in functional vasoconstriction via ET-1 receptor in rat ophthalmic and pig retinal arteries. Furthermore, this study is the first to suggest a way of inhibiting and preventing such an increase. With these results, we suggest a novel approach in retinal ischaemia therapy.</p>},
  author       = {W Blixt, Frank and Kristian Haanes, Agmund and Ohlsson, Lena and Tolstrup Christiansen, Anders and Warfvinge, Karin and Edvinsson, Lars},
  issn         = {1755-3768},
  language     = {eng},
  month        = {01},
  number       = {5},
  pages        = {619--625},
  publisher    = {Wiley-Blackwell},
  series       = {Acta Ophthalmologica},
  title        = {Increased endothelin-1-mediated vasoconstriction after organ culture in rat and pig ocular arteries can be suppressed with MEK/ERK1/2 inhibitors},
  url          = {http://dx.doi.org/10.1111/aos.13651},
  doi          = {10.1111/aos.13651},
  volume       = {96},
  year         = {2018},
}