Abstract
Visual impairment and blindness are often caused by retinal ischemia-reperfusion (I/R) injury. We aimed to characterize a new model of I/R in pigs, in which the intraocular pathways were not manipulated by invasive methods on the ocular system. After 12 min of ischemia followed by 20 h of reperfusion, reactivity of retinal arterioles was measured in vitro by video microscopy. Dihydroethidium (DHE) staining, qPCR, immunohistochemistry, quantification of neurons in the retinal ganglion cell layer, and histological examination was performed. Retinal arterioles of I/R-treated pigs displayed marked attenuation in response to the endothelium-dependent vasodilator, bradykinin, compared to sham-treated pigs. DHE staining intensity and messenger RNA levels for HIF-1α, VEGF-A, NOX2, and iNOS were elevated in retinal arterioles following I/R. Immunoreactivity to HIF-1α, VEGF-A, NOX2, and iNOS was enhanced in retinal arteriole endothelium after I/R. Moreover, I/R evoked a substantial decrease in Brn3a-positive retinal ganglion cells and noticeable retinal thickening. In conclusion, the results of the present study demonstrate that short-time ocular ischemia impairs endothelial function and integrity of retinal blood vessels and induces structural changes in the retina. HIF-1α, VEGF-A, iNOS, and NOX2-derived reactive oxygen species appear to be involved in the pathophysiology.
Highlights
Ischemia-reperfusion (I/R) events represent a major reason for various retinal disorders [1,2]
By analyzing mRNA expression levels of all three nitric oxide synthase isoforms (NOS), we found that I/R raised expression for inducible NOS by ≈ 2.2-fold (* p < 0.05), whereas the expression for endothelial and neuronal NIntO
Retinal ischemia can be triggered by two vessel occlusion (2VO), termed bilateral common carotid arteries occlusion (BCCAO), leading to a 50% retinal ischemia, as well as by combined occlusion of vertebral arteries and common carotid arteries, called four vessel occlusion (4VO), resulting in complete retinal ischemia of 95–100% [25], which is the case in the present study
Summary
Ischemia-reperfusion (I/R) events represent a major reason for various retinal disorders [1,2]. Arterial fibrinolysis has failed to improve the clinical outcome of CRAO compared to conservative treatment (e.g., aspirin, ocular massage) or was even shown to be harmful [5,6] These studies suggest that deleterious, yet poorly understood, molecular processes are activated already in the early phase of retinal ischemia. Raising intraocular pressure by cannulation of the anterior chamber and administering saline solution leads to complete occlusion of retinal and ciliary vessels and represents a favorable method to investigate overall alterations within the ocular system due to complete ischemia. An advantage of this method is that it does not require much equipment or technical expertise. Application of endothelin-1 represents a non-invasive method to induce endogenous vasoconstriction of vessels, it affects physiological pathways by binding to ETA and ETB receptors, which may induce direct release of cytokines and ROS [18]
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