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X. Wang, J. McKenzie, S. E. Moss, J. Greenwood; Characterization of a Novel Leucine-Rich Repeat Glycoprotein (Rts1) in Retinal Vascular Remodelling. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3341.
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Remodelling of the retinal vasculature is a key feature of sight-threatening conditions such as diabetic retinopathy, retinopathy of prematurity and macular telangiectasia (MacTel). These vascular changes manifest themselves as both new capillary growth from pre-existing retinal vessels (angiogenesis) and the development of vascular malformations of existing vessels (e.g. microaneurysms, telangiectasia). The ami of the current project is to identify novle molecular determinants that contribute to the vascular remodelling observed in these diseases and to identify potential therapeutic targets.
Differential gene expression analysis was carried out on microvessels isolated from wild-type (WT) controls and from three mouse models of retinal disease which exhibit vascular remodelling (VLDLR-/-, RD1 and Curly tail). Changes in 63 genes that were common to all three models of vascular remodelling were identified.
Genome-wide expression profiling revealed that the expression of a novel member of the Leucine-rich Repeat Protein family, that we have termed regulator of TGFbeta signalling-1 (Rts1), is significantly up-regulated in the retinal vasculature of all tested mouse models. The increased expression was confirmed by quantitative RT-PCR. RNA in situ hybridization revealed that Rts1 is predominantly expressed in the retinal vasculature and immunehistochemistry shows that Rts1 protein decorates retinal blood vessels. Moreover, Rts1 protein level is significantly higher in the mouse models of vascular remodelling studied compared to wild type. Co- immunoprecipitation results suggest a direct interaction between Rts1 and the TGFbeta receptor complex. We have also shown that Rts1 promotes angiogenesis through regulating the TGFbeta signalling pathway in vitro.
Together, these results indicate an important role for Rts1 in retinal vascular remodelling. We hypothesise that it may be involved in switching TGFbeta signalling from anti-angiogenic to pro-angiogenic pathway in endothelial cells and that its up-regulation contributes to angiogenesis and /or vessel remodelling.This work was funded by the Lowy Medical Research Institute Ltd. (The Macular Telangiectasia Project, www.mactelresearch.com)
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