title: Myeloid cells expressing VEGF and arginase-1 following uptake of damaged retinal pigment epithelium suggests potential mechanism that drives the onset of choroidal angiogenesis in mice.
abstract: Whilst data recognise both myeloid cell accumulation during choroidal neovascularisation (CNV) as well as complement activation, none of the data has presented a clear explanation for the angiogenic drive that promotes pathological angiogenesis. One possibility that is a pre-eminent drive is a specific and early conditioning and activation of the myeloid cell infiltrate. Using a laser-induced CNV murine model, we have identified that disruption of retinal pigment epithelium (RPE) and Bruch's membrane resulted in an early recruitment of macrophages derived from monocytes and microglia, prior to angiogenesis and contemporaneous with lesional complement activation. Early recruited CD11b(+) cells expressed a definitive gene signature of selective inflammatory mediators particularly a pronounced Arg-1 expression. Accumulating macrophages from retina and peripheral blood were activated at the site of injury, displaying enhanced VEGF expression, and notably prior to exaggerated VEGF expression from RPE, or earliest stages of angiogenesis. All of these initial events, including distinct VEGF (+) Arg-1(+) myeloid cells, subsided when CNV was established and at the time RPE-VEGF expression was maximal. Depletion of inflammatory CCR2-positive monocytes confirmed origin of infiltrating monocyte Arg-1 expression, as following depletion Arg-1 signal was lost and CNV suppressed. Furthermore, our in vitro data supported a myeloid cell uptake of damaged RPE or its derivatives as a mechanism generating VEGF (+) Arg-1(+) phenotype in vivo. Our results reveal a potential early driver initiating angiogenesis via myeloid-derived VEGF drive following uptake of damaged RPE and deliver an explanation of why CNV develops during any of the stages of macular degeneration and can be explored further for therapeutic gain.
authors: Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors: Jian
authors: J
authors: Liu
authors: David A
authors: DA
authors: Copland
authors: Shintaro
authors: S
authors: Horie
authors: Wei-Kang
authors: WK
authors: Wu
authors: Mei
authors: M
authors: Chen
authors: Yunhe
authors: Y
authors: Xu
authors: B
authors: B
authors: Paul Morgan
authors: Matthias
authors: M
authors: Mack
authors: Heping
authors: H
authors: Xu
authors: Lindsay B
authors: LB
authors: Nicholson
authors: Andrew D
authors: AD
authors: Dick
mesh_terms: D000818:Animals; D001119:Arginase; D016570:Bruch Membrane / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D049109:Cell Proliferation; D020256:Choroidal Neovascularization / Q000235:genetics / Q000473:pathology*; D004249:DNA Damage; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D017075:Laser Coagulation; D008264:Macrophages / Q000473:pathology; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology; D009000:Monocytes / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D010641:Phenotype; D054390:Receptors, CCR2 / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D054390:Receptors, CCR2; D042461:Vascular Endothelial Growth Factor A; D001119:Arginase
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