Journal
NATURE
Volume 499, Issue 7458, Pages 306-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature12345
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Funding
- Lowy Medical Research Foundation
- Medical Research Council
- Wellcome Trust
- UCL Business (Proof of Concept Grant)
- Rosetrees Trust
- NIHR Research Professorship
- British Heart Foundation Senior Fellowship
- MRC [G1000466, G0902206] Funding Source: UKRI
- British Heart Foundation [RG/12/2/29416] Funding Source: researchfish
- Medical Research Council [G0902206, G1000466] Funding Source: researchfish
- National Institute for Health Research [NIHR-RP-011-003] Funding Source: researchfish
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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-beta 1 (TGF-beta 1), 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-beta accessory receptor endoglin, which, in the presence of TGF-beta 1, 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-beta signalling.
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