Abstract
Purpose: :
Macular Telangiectasia (MacTel) is a progressive bilateral disorder affecting the retinal vasculature, in which the retinal blood vessels become tortuous, dilated and leaky. End-stage disease includes subretinal neovascularisation and substantial loss of central vision.
Methods: :
In order to identify candidate genes that drive the formation of these abnormal vessels, we selected several animal models of retinal telangiectasia (The Royal College of Surgeons (RCS) rat, very low density lipoprotein receptor (VLDLR) knock-out mouse, curly tail mouse and retinal degeneration 1 (RD1) mouse) and performed a microarray analysis on microvessel fragments from the retinae of these and control animals.
Results: :
Microvessels were successfully isolated from the mouse and rat retinae using magnetic beads, and the presence of endothelial cells and pericytes in this fraction was confirmed by quantitative real time PCR (q-PCR) and western blotting. RNA was extracted from the microvessels for the microarray analysis. In all, sixty three genes were found that are differentially expressed across all animal models examined. Among the up-regulated genes were the G-protein coupled receptor, APJ/AGTRL1, and its secreted ligand, apelin. Elevated APJ expression levels were validated by q-PCR and western blotting, and increased apelin mRNA was also confirmed by q-PCR. Consistent with these findings, APJ was shown to localise to the retinal vasculature in the RCS rat. Apelin knock-out mice have been crossed to VLDR knock-out mice, as well as to RD1 mice and offspring will be examined for a reduction of retinal telangiectasia. Experiments are also underway to examine APJ signalling mechanisms in endothelial cells in vitro, and to develop new approaches to therapeutically inhibit apelin/APJ pathways.
Conclusions: :
APJ/apelin signalling has previously been implicated in angiogenesis, and the apelin knock-out mouse has recently been shown to exhibit retinal vascular abnormalities. Microarray analysis in mice and rats with telangiectasia indicates that an upregulation of APJ/apelin signalling may be involved in the formation of retinal telangiectasia. APJ/apelin signalling may thus represent a novel therapeutic target for the treatment of retinal telangiectasia.
Keywords: retinal neovascularization • retina • gene microarray