Publication Date:
2013-07-23
Description:
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-beta1 (TGF-beta1), 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-beta1, 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836402/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836402/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiaomeng -- Abraham, Sabu -- McKenzie, Jenny A G -- Jeffs, Natasha -- Swire, Matthew -- Tripathi, Vineeta B -- Luhmann, Ulrich F O -- Lange, Clemens A K -- Zhai, Zhenhua -- Arthur, Helen M -- Bainbridge, James W B -- Moss, Stephen E -- Greenwood, John -- 091886/Wellcome Trust/United Kingdom -- G0902206/Medical Research Council/United Kingdom -- G1000466/Medical Research Council/United Kingdom -- NIHR-RP-011-003/Department of Health/United Kingdom -- RG/12/2/29416/British Heart Foundation/United Kingdom -- British Heart Foundation/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Jul 18;499(7458):306-11. doi: 10.1038/nature12345.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23868260" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cells, Cultured
;
Endothelium, Vascular/cytology/*metabolism
;
Glycoproteins/genetics/metabolism/*physiology
;
In Vitro Techniques
;
Mice
;
Mice, Inbred C57BL
;
Mice, Knockout
;
Receptors, Transforming Growth Factor beta/metabolism
;
Retinal Neovascularization/genetics/*metabolism
;
Retinal Vessels/metabolism
;
*Signal Transduction
;
Transforming Growth Factor beta1/*metabolism/pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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