title: LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling.
abstract: Aberrant neovascularization contributes to diseases such as cancer, blindness and atherosclerosis, and is the consequence of inappropriate angiogenic signalling. Although many regulators of pathogenic angiogenesis have been identified, our understanding of this process is incomplete. Here we explore the transcriptome of retinal microvessels isolated from mouse models of retinal disease that exhibit vascular pathology, and uncover an upregulated gene, leucine-rich alpha-2-glycoprotein 1 (Lrg1), of previously unknown function. We show that in the presence of transforming growth factor-β1 (TGF-β1), LRG1 is mitogenic to endothelial cells and promotes angiogenesis. Mice lacking Lrg1 develop a mild retinal vascular phenotype but exhibit a significant reduction in pathological ocular angiogenesis. LRG1 binds directly to the TGF-β accessory receptor endoglin, which, in the presence of TGF-β1, results in promotion of the pro-angiogenic Smad1/5/8 signalling pathway. LRG1 antibody blockade inhibits this switch and attenuates angiogenesis. These studies reveal a new regulator of angiogenesis that mediates its effect by modulating TGF-β signalling.
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Sabu
authors.initials: S
authors.lastname: Abraham
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Jenny A G
authors.initials: JAG
authors.lastname: McKenzie
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Natasha
authors.initials: N
authors.lastname: Jeffs
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Swire
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Vineeta B
authors.initials: VB
authors.lastname: Tripathi
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Ulrich F O
authors.initials: UFO
authors.lastname: Luhmann
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK.|NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, UK.|University Eye Hospital Freiburg, Freiburg, Germany.
authors.forename: Clemens A K
authors.initials: CAK
authors.lastname: Lange
authors.affiliation: Institute of Genetic Medicine, Newcastle University, UK.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Zhai
authors.affiliation: Institute of Genetic Medicine, Newcastle University, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Arthur
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK.|NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bainbridge
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Moss
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: John
authors.initials: J
authors.lastname: Greenwood
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D006023:Glycoproteins; C530631:LRG1 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1