March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Leucine-rich Alpha-2 Glycoprotein 1 (Lrg1) Contributes To The Development Of Ocular Neovascularisation
Author Affiliations & Notes
  • Xiaomeng Wang
    Cell Biology, Institute of Ophthalmology, UCL, London, United Kingdom
  • Jenny McKenzie
    Cell Biology, Institute of Ophthalmology, UCL, London, United Kingdom
  • Natasha R. Jeffs
    Cell Biology, UCL, London, United Kingdom
  • Sabu Abraham
    Cell Biology, Institute of Ophthalmology, UCL, London, United Kingdom
  • Matthew Swire
    Cell Biology, Institute of Ophthalmology, UCL, London, United Kingdom
  • Clemens A. Lange
    Genetics, Cell Biology,
    Institute of Ophthalmology, London, United Kingdom
  • James W. Bainbridge
    UCL Institute of Ophthalmology, London, United Kingdom
  • Stephen E. Moss
    Cell Biology,
    Institute of Ophthalmology, London, United Kingdom
  • John Greenwood
    Genetics, Cell Biology,
    UCL Institute of Ophthalmology, London, United Kingdom
  • Footnotes
    Commercial Relationships  Xiaomeng Wang, None; Jenny McKenzie, None; Natasha R. Jeffs, None; Sabu Abraham, None; Matthew Swire, None; Clemens A. Lange, None; James W. Bainbridge, None; Stephen E. Moss, None; John Greenwood, None
  • Footnotes
    Support  Lowy Medical Research Institute Ltd, the MRC and a UCLB POC Award
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2995. doi:https://doi.org/
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      Xiaomeng Wang, Jenny McKenzie, Natasha R. Jeffs, Sabu Abraham, Matthew Swire, Clemens A. Lange, James W. Bainbridge, Stephen E. Moss, John Greenwood; Leucine-rich Alpha-2 Glycoprotein 1 (Lrg1) Contributes To The Development Of Ocular Neovascularisation. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2995. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Aberrant angiogenesis is the hallmark of many blinding eye diseases including retinopathy of prematurity, proliferative diabetic retinopathy, age-related wet macular degeneration (AMD) and macular telangiectasia. The formation of new vessels is a complex and tightly regulated process involving multiple intercellular pro- and anti-angiogenic molecules. We have previously demonstrated that leucine rich α-2-glycoprotein-1 (Lrg1) is involved in the fine-tuning of angiogenesis and drives this delicate process in a pro-angiogenic direction. The aim of this study was to gain new insight into the molecular mechanisms of Lrg1 signalling and its interaction with other signalling pathways involved in angiogenesis, as well as to evaluate its potential as a therapeutic target.

Methods: : Co-immunoprecipitation and GST-pulldown assay were used to identify Lrg1 binding proteins. The interaction between Lrg1 and the TGFβ signalling pathway in angiogenesis was studied in vitro (proliferation assay and organotypic angiogenesis assay), ex vivo (metatarsal assay and aortic ring assay) and in vivo. The therapeutic potential of a Lrg1 neutralizing antibody was studied in vitro (Matrigel assay) and in vivo (mouse model of wet AMD).

Results: : We observed that Lrg1 interacts with TGFβ1 and its receptors in vitro. Recombinant human Lrg1 (rhLrg1) promotes TGFβ1 stimulated Smad1/5 phosphorylation and subsequent endothelial cell (EC) proliferation. rhLrg1 and TGFβ1 promote vessel outgrowth from metatarsal and aortic ring explants, which could be attenuated by polyclonal antibody against full length human Lrg1 protein. Lrg1 neutralizing antibody completely blocks HUVEC tube formation in Matrigel and inhibits laser induced choroidal neovascularization.

Conclusions: : This study demonstrates that Lrg1 plays an important role in angiogenesis through regulating the TGFβ signalling pathway and is a potentially promising therapeutic target.

Keywords: choroid: neovascularization • neovascularization • retinal neovascularization 
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