Potential Role of Microglia in Retinal Blood Vessel Formation

Checchin, Daniella; Sennlaub, Florian; Levavasseur, Etienne; Leduc, Martin; Chemtob, Sylvain

doi:10.1167/iovs.05-1522

Cited by 305 publications

(288 citation statements)

References 59 publications

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“…52 Basal levels of microglial activity are essential for maintaining retinal homeostasis, including normal vascularization of the retina. 53 However, their hyperactivation is implicated in the progression of many diseases, including DR. 54 Hyperactivation is characterized by the release of toxic molecules (TNF-a, IL-1b, O 2 À , and nitric oxide) that are intended to destroy offending pathogens. 54,55 In fact, microglia are considered the early primary source of IL-1 in central nervous system injury, infection, and inflammation.…”

Section: Retinal Overexpression Of Ace2 May Suppress Proinflammatory mentioning

confidence: 99%

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Dominguez

Caballero

et al. 2016

The American Journal of Pathology

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Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)eACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein (GFP)echimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrowederived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP þ cells was used to measure leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 AE 1.4; ACE2 diabetic, 6.4 AE 0.9 per mm 2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 AE 1.9; ACE2 diabetic, 6.5 AE 1.2 per mm 2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80 þ ) (prevention cohort: untreated diabetic, 24.2 AE 6.7; ACE2 diabetic, 2.5 AE 1.6 per mm 2 ; reversal cohort: untreated diabetic, 56.8 AE 5.2; ACE2 diabetic, 5.6 AE 2.3 per mm 2 ). In both study cohorts, intracapillary bone marrowederived cells, indicative of leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system. (Am J Pathol 2016, 186: 1688e1700; http://dx

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Section: Retinal Overexpression Of Ace2 May Suppress Proinflammatory mentioning

confidence: 99%

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Dominguez

Caballero

et al. 2016

The American Journal of Pathology

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“…Retinal and RPE/choroidal flatmounts were stained according to previously described standard immunohistochemical procedures. 15 The primary antibodies and lectins used were Bandeirae simplicifolia lectin (Sigma-Aldrich, Saint Quentin Fallavier, France), goat anti-mouse IL-1␤ (R&D Systems, Lille, France), rabbit polyclonal anti-IL-1RI (Santa Cruz Biotechnology Inc., Heidelberg, Germany), rabbit polyclonal anti-Iba1 (Wako, Neuss, Germany), rat anti-mouse Ly6G (Miltenyi Biotec, Paris, France), and goat anti-human Collagen IV (R&D Systems). The corresponding Alexa secondary antibodies (Molecular Probes, Leiden, The Netherlands) were used to show the primary antibodies, and flatmounts were counterstained with DAPI.…”

Section: Choroidal Flatmounts Ihc and Cnv Quantificationsmentioning

confidence: 99%

Interleukin-1β Inhibition Prevents Choroidal Neovascularization and Does Not Exacerbate Photoreceptor Degeneration

Lavalette

Raoul

Houssier

et al. 2011

The American Journal of Pathology

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106

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“…Although several cell types can produce TNF-α, monocyte-derived cells are a major source 20 . Microglia, macrophages and dendritic cells are Csf1r + inflammatory cells that are critical to the development and repair of the retinal vasculature 21,22 . To determine whether these cells or vascular endothelial cells produce TNF-α in retinopathy, we immunohistochemically labeled and localized TNF-α, Csf1r and vascular endothelial cells with confocal microscopy in retinal whole-mounts from mice on an ω-6-PUFA diet (Fig.…”

mentioning

confidence: 99%

“…EPA, DHA and their potent bioactive products (NPD1, RvD1 and RvE1) at physiological levels reduce pathologic neovascularization through enhanced vessel regrowth after vascular loss and injury. Macrophages or microglia are a critical component of retinal vascular growth and repair 21,22 . In the retina, increased dietary ω-6-PUFA (arachidonic acid) increases activated microglial production of TNF-α, which is suppressed with elevated ω-3-PUFA levels (DHA, EPA).…”

mentioning

confidence: 99%

Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis

Connor

SanGiovanni

Löfqvist

et al. 2007

Nat Med

627

572

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Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of ω-3-and ω-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy 1 . We show that increasing ω-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissionsCorrespondence should be addressed to L.E.H.S. (lois.smith@childrens.harvard.edu).. Supplementary information is available on the Nature Medicine website. COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http:// www.nature.com/naturemedicine/. HHS Public AccessAuthor manuscript Nat Med. Author manuscript; available in PMC 2015 July 05. Published in final edited form as:Nat Med. 2007 July ; 13(7): 868-873. doi:10.1038/nm1591. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive ω-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of ω-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-α. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of ω-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in ω-3-PUFA, and premature infants lack the important transfer from the mother to the infant of ω-3-PUFA that normally occurs in the third trimester of pregnancy 2 . Supplementing ω-3-PUFA intake may be of benefit in preventing retinopathy.Ocular neovascularization is the most common cause of blindness in all age groups: retinopathy of prematurity in children, diabetic retinopathy in working-age adults and agerelated macular degeneration in the elderly. In principle, destructive angiogenesis in the eye can be ameliorated by either direct inhibition of neovascularization or by controlling vessel loss in order to reduce the hypoxic stimulus that drives neovascularization. Retinopathy is modeled in the mouse eye with oxygen-induced vessel loss, which precipitates hypoxiainduced retinopathy, allowing for assessment of retinal vessel loss, vessel regrowth after injury and pathological angiogenesis 1 .The role of lipids in angiogenesis is just beginning to be defined 3,4 . The major polyunsaturated fatty acids (PUFA) found in the retina a...

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Potential Role of Microglia in Retinal Blood Vessel Formation

Cited by 305 publications

References 59 publications

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Interleukin-1β Inhibition Prevents Choroidal Neovascularization and Does Not Exacerbate Photoreceptor Degeneration

Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis

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