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Xiaomeng Wang, Jenny McKenzie, Clemens Lange, James Bainbridge, Stephen E. Moss, John Greenwood; Leucine-rich Repeat Glycoprotein (Lrg1) Contributes To The Development Of Ocular Neovascularisation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3115. doi: https://doi.org/.
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Aberrant remodelling of retinal/choroidal vasculature, leads to vascular malformations of existing vessels (e.g. microaneurysms and telangiectasia) as well as the growth of new blood vessels from pre-existing vessels (neoangiogenesis), which are hallmarks of sight-threatening conditions such as diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration and macular telangiectasia. The objective of the current project is to characterize the involvement of a novel member of the leucine-rich repeat family protein Lrg1 in pathological vascular remodelling and neoangiogenesis, and evaluate its potential as a therapeutic target.
Real time quantitative RT-PCR and semi-quantitative Western Blotting were used to measure changes in expression levels of Lrg1 in the eye of disease mouse models and human patients with proliferative diabetic retinopathy (PDR). Whole-mount in situ hybridization and immunohistochemistry was performed to evaluate the expression pattern of Lrg1 in mouse retina. The role of Lrg1 in vascular remodelling and angiogenesis was studied in vitro (matrigel angiogenesis assay, proliferation assay), ex vivo (metatarsal assay) and in vivo (oxygen induced retinopathy (OIR) and choroidal neovascularisation (CNV) in mice).
Lrg1 expression is significantly up-regulated in retinas of mouse models with abnormal vascular remodelling and angiogenesis. Its protein level is much higher in vitreous of human patients with PDR compared to that in non-PDR patients. RNA in situ hybridization revealed that Lrg1 is predominantly expressed in the retinal vasculature and immunohistochemistry showed that Lrg1 protein decorates retinal blood vessels. Lrg1 promotes endothelial cell proliferation, tube formation and vessel outgrowth in vitro and ex vivo assays. Endothelial cell tube formation in matrigel was inhibited by a polyclonal antibody directed against full-length Lrg1 protein. In a mouse model of OIR, loss of Lrg1 resulted in a significant reduction of pathogenic neovascularization but with retention of normal physiological vessel regrowth. In laser-induced CNV absence of Lrg1 also led to attenuation of neovascularisation.
This study demonstrates that Lrg1 plays an important role in pathologenic vascular remodelling and neoangiogenesis and may serve as a potential therapeutic target for the treatment of eye diseases such as AMD and PDR.
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