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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
Author(s) -
Blixt Frank W.,
Haanes Kristian Agmund,
Ohlsson Lena,
Tolstrup Christiansen Anders,
Warfvinge Karin,
Edvinsson Lars
Publication year - 2018
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/aos.13651
Subject(s) - vasoconstriction , downregulation and upregulation , electrical impedance myography , immunohistochemistry , receptor , vascular smooth muscle , retinal , endothelin 1 , endothelin receptor , organ culture , medicine , myograph , endocrinology , pharmacology , artery , biology , smooth muscle , vasodilation , ophthalmology , biochemistry , gene , in vitro
Purpose Even though retinal vascular changes following ischaemia have been poorly understood, the upregulation of vasoconstrictive endothelin‐1 (ET‐1) receptors (ET A /ET B ) 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 ET A and ET B receptors 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 ET B receptor. 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 ET B expression 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.