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Shilpa Dasari, Josephine V. Glenn, Mei Chen, Liza Colhoun, Michael Quinn, Heping Xu, Angelika Bierhaus, Alan W. Stitt; RAGE-S100B Ligand Interactions Play An Important Regulatory Role In Angiogenesis Invitro And Choroidal Neovascularization (CNV) Invivo. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1801.
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© ARVO (1962-2015); The Authors (2016-present)
The receptor for AGEs (RAGE) binds to a range of ligands to evoke pro-inflammatory signaling responses in diverse cells and tissues. This study has investigated how RAGE and its ligands modulate key processes that lead to CNV.
C57Bl/6 control (WT) and RAGE null (RAGE-/-) mice, (12 wks, n=12/group) underwent diode laser photocoagulation to generate CNV lesions. Fundus photography and cSLO images of Indocyanine green angiography were used to evaluate lesions. Post-mortem, eyes were enucleated 7 days post laser exposure and retinal flat-mounts analyzed for CNV lesion morphology, occurrence of the RAGE-ligand S100B and inflammatory cell infiltration. In a parallel in vitro study with human endothelial cells (HMEC-1), the angiogenic response (cell migration and tubulogenesis in Matrigel®) of S100B was assessed. siRNA was then used to knockdown RAGE expression in HMEC-1 and S100B-mediated angiogenesis, NFΚB transcription and PI3K / Akt phosphorylation were analyzed.
Retina from RAGE -/- mice exhibited significantly reduced CNV lesion size when compared to WT controls (p<0.05) (n=12/group). Activated microglia were considerably less abundant in CNV lesions from RAGE-/- mice when compared to WT counterparts (p<0.001). S100B immunostaining was high around the CNV lesions of WT mice when compared to those in RAGE-/- mice. S100B-treated HMEC-1 cells showed increased migration and tube formation (p<0.001) phosphorylation of the Akt (PI3K) pathways and subsequent NFΚB transcriptional activation. siRNA mediated knockdown of RAGE significantly prevented all these HMEC-1 responses to S100B.
RAGE plays an important role in CNV lesion formation. Pro-inflammatory and angiogenic responses appear to be mediated by S100B-RAGE interactions. This study highlights the role of RAGE in inflammation-mediated outer retinal pathology.
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