Abstract
Purpose: :
Idiopathic Juxtafoveal Macular Telangiectasia (MacTel) is a condition originally characterized by the presence of dilated and incompetent blood vessels around the fovea and is of unknown aetiology. This condition leads to loss of central vision over a period of 10-20 years. The aim of the current project is to identify key molecular determinants that drive the vascular remodelling observed in MacTel. This will help us to further characterize the disease and identify novel therapuetic targets.
Methods: :
Differential gene expression analysis was carried out on microvessels isolated from three mouse models of retinal degeneration (VLDLR-/-, RD1 and Curly tail), which exhibit telangiectatic vessel formation compared to wild-type control. 63 common genes were identified in telangiectatic vessels.
Results: :
Genome-wild expression profiling revealed that the expression of leucine-rich alpha-2-glycoprotein 1 (Lrg1) is significantly up-regulated in the retinal vasculature of all tested mouse models. Lrg1 has been associated with TGFβ1 and TbetaR-II in cancer and dysfunction of TGFβ signalling leads to Hemorrhagic hereditary telangiectasia (HHT). RNA in situ hybridization revealed that Lrg1 is specifically expressed in the retinal vasculature and up-regulated Lrg1 expression in telangiestasia mouse models has been confirmed by quantitative PCR. Immunohistochemistry shows that Lrg1 protein accumulates in retinal blood vessels and that Lrg1 protein level is significantly higher in telangiestasia mouse models compared to wild-type mice. We also show the interaction between Lrg1 and TGFβ signalling pathway in vitro.
Conclusions: :
Together, these results suggest an important role for Lrg1 in retinal telangiectasia. We hypothesise that it may act as a negative regulator of the TGFβ signalling pathway in endothelial cells and that its up-regulation hence leads to angiogenesis.
Keywords: retinal neovascularization • gene/expression • growth factors/growth factor receptors