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C. J. Breen, T. Gardiner, A. Stitt, T. Cogliati; Microglia and Angiogenesis in the Developing Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):29.
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© ARVO (1962-2015); The Authors (2016-present)
Microglia (MG) invade the immature retina prior to angiogenesis. MG are capable of producing a battery of inflammatory mediators, as well as angiogenic cytokines, but in the developing retina they assume a benign phenotype that is not associated with inflammation. During retinal vascularisation MG can be observed in close proximity to endothelial tip cells of the growing vascular tree. Furthermore, they phagocytose surplus cells undergoing apoptosis, potentially eliciting an anti-inflammatory, yet pro-angiogenic response. In this study, we examined the potential of MG to induce angiogenesis using in-vivo and in-vitro approaches.
Eyes from C57BL/6 mice between postnatal day-0 (P0) and P12 were collected and RNA extracted to examine expression patterns of angiogenic and inflammatory cytokines. Sectioned and flat mounted eyes were also double stained with Tomato Lectin and Cleaved-Caspase 3 to study the uptake of MG to apoptotic cells. BV2 MG cells in vitro were fed apoptotic bodies generated from cultured WERI-Rb1 retinoblastoma cells and changes in angiogenic and inflammatory cytokine expression were analyzed. Finally, conditioned media from BV2 cells either fed apoptotic bodies or treated with LPS were compared in a Matrigel angiogenesis assay.
During retinal vascular development Caspase-3 / Lectin staining revealed activated MG actively phagocytosing apoptotic cells, often in close apposition to endothelial tip cells. In-vivo, expression of VEGF, SDF1, IL10, TNFalpha and MIP1alpha were maximal at P6 and coincident with waves of apoptosis. Upon ingestion of apoptotic cells, BV2 cell expression of VEGF and IL10 increased two-fold while TNFalpha and MIPalpha were unchanged; conditioned media increased angiogenic sprouts in the Matrigel assay compared to controls (p<0.01).
Ingestion of apoptotic bodies by MG in-vitro causes up-regulation of angiogenic and anti-inflammatory cytokines and induces angiogenesis. In-vivo, MG phagocytosis of apoptotic cells in the developing retina may be anti-inflammatory and promote angiogenesis.
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