Abstract
Purpose :
Substantial efforts have been made over the last three decades to understand the biochemical mechanisms involved in ischemic retinal damage and to develop potential remedies to protect the retina. However, the search for treatments of retinal ischemia has been disappointing, despite immense efforts over the years. Thus, it is necessary to reconsider the premises upon which these failed treatments were developed and find novel ways to understand and treat retinal ischemia. Our focus in this experiment is on the vascular wall of the ophthalmic artery of rat and porcine retinal arteries. We believe that the key to ischemic treatment is found here. Previously it has been proposed that the MEK/ERK1/2 cellular mechanism is involved in the upregulation of endothelin-1 (ET-1) receptors ETA/B after cerebral ischemia. We postulate that the inhibition of this mechanism using U0126 (a specific ERK1/2 inhibitor) will attenuate the vasoconstriction following ischemia in both the ophthalmic artery in rat and retinal arteries in pig.
Methods :
Organ culture allows for in vitro depiction of ischemic conditions. Therefore rat ophthalmic arteries and porcine retinal arteries underwent 24 hours of organ culture followed by myograph functional evaluations. Furthermore, U0126 was added to the culture medium in order to prevent upregulation of ET-1. Immunohistochemistry was performed on vessels to illustrate arterial expression of ET-1 receptors ETA/B and the activation of the MEK/ERK1/2 pathway.
Results :
Both porcine retinal arteries and rat ophthalmic artery showed significant increase of ET-1 mediated vasoconstriction after 24 hour organ culture. Furthermore, this was completely reduced by the administration of U0126. Immunohistochemistry revealed the activation of ERK1/2 and the distribution of ET-1 receptors ETA/B in the vascular smooth muscle wall.
Conclusions :
This is the first study which shows that the ET-1 mediated vasoconstriction in porcine retinal arteries can be diminished using a MEK/ERK1/2 inhibitor. Additionally, rat ophthalmic arteries followed the same pattern. With these results we hope to shift the attention of treatment studies towards the vasculature in an effort to gather a fresh perspective on treatment. This study also suggest that the MEK/ERK1/2 mechanism may be the target of future therapeutic agents after retinal ischemia.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.