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Ryan Delaney, Carmel McVicar, Mei Chen, Alan W Stitt; Modulatory role of S100B during retinal angiogenesis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3393.
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© ARVO (1962-2015); The Authors (2016-present)
S100 calcium binding protein B (S100B) is a neurotrophic factor that regulates cytosolic Ca2+ and cytoskeletal integrity in astrocytes, neural progenitors and dendritic cells. In retina, S100B is exclusively expressed by glia and recent studies from our group have demonstrated that glial-linked S100B is increased in choroidal neovascularisation via the receptor for advanced glycation endproducts (RAGE). We sought to investigate if S100B was proangiogenic in the retinal vasculature by studying developmental and pathological blood vessel growth.
S100B expression levels were assessed during stages of retinal development (P1 to 25) in wild-type (WT) C57BL/6 using qPCR. This was correlated with the presence of S100B-positive astrocytes and formation of vascular plexuses using confocal microscopy of flat-mount retinas. Oxygen-induced retinopathy (OIR) was also induced in WT and RAGE-/- mice. In parallel, the role of extracellular S100B in angiogenesis was investigated using tube formation assays after RAGE expression was ablated using siRNA or VEGF neutralised using Ranibizumab.
During normal developmental angiogenesis the number of S100B positive astrocytes was increased at the early stage of retinal development, reaching a peak at P7 (790/mm2 retina), then reduced gradually (P12=350/mm2 retina). In OIR, S100B-positive astrocytes alter their shape in the ischemic retina compared to non-positive cells. S100B immunoreactivity was intense in the active neovascular fronds. RAGE-/- mice demonstrated reduced ischaemia and less pre-retinal neovascularisation compared to WT controls (p<0.001). In vitro, S100B stimulation induced endothelial tube formation compared to controls (p<0.001), which was a VEGF-dependent response. Likewise, RAGE siRNA treatment significantly inhibited the S100B tube-forming response.
S100B is a pro-angiogenic factor which exerts its effect, at least in part, via VEGF and requiring RAGE signalling. S100B plays an important modulatory role in developmental and pathological angiogenesis.
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