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N. Unoki, T. Murakami, K. Nishijima, N. Yoshimura; Stromal Cell-Derived Factor-1 (SDF-1) / CXCR4 Promotes the Activation of Tip Cells and Microglia in Retinal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2935.
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© ARVO (1962-2015); The Authors (2016-present)
Although stromal cell-derived factor-1 (SDF-1) contributes to angiogenesis, its effects upon sprouting angiogenesis remain ill-defined. We investigated how SDF-1 and its receptor, CXCR4, regulate the tip cells and microglia in neovascular sprouting.
The retinas isolated from 7- to 8- week old C57BL6/J mice were cultured for 96 hours with or without inhibitors, and applied to each experiment. For in vivo experiments, inhibitors were intraperitoneally administrated into C57BL6/J mice on postnatal day 2 (P2), and the eyes were isolated on P4. After the fixation and permeation, immunostaining with fluorescent 2nd antibody were performed. To quantify the transcriptional levels, mRNA was applied to reverse transcription and following real time PCR. Time-sequential images were obtained at every 15 minute intervals, using confocal microscopy. The movements of tip cells and microglia were quantified.
Neutralizing antibodies against SDF-1 or an antagonist of CXCR4, AMD3100, decreased the radius of the vascularized area in retinal vascular development. These inhibitions disturbed the filopodial extensions in tip cells and decreased the mRNA levels of KDR/Flk-1, UNC5B, and PDGFB, which are highly expressed in tip cells. In ex vivo experiments, VEGF increased SDF-1 mRNA expression, and the inhibition of SDF-1/CXCR4 decreased the number of VEGF-induced neovascular sprouts. We investigated the kinetics of sprouts using time-lapse imaging, and found that SDF-1/CXCR4 contributes to the elongation of neovascular sprouts and also to the motility of leading edges in tip cells. These data deomonstrate that SDF-1/CXCR4 promotes the sprouting angiogenesis per se. In addition, the number of microglia in in vivo neonatal retinas was reduced by SDF-1/CXCR4 inhibitons. The movements of resident microglia by VEGF treatment were also reduced by these inhibitions, suggesting this axis contributes to the activation of microglia partially.
These data suggests that SDF-1/CXCR4 promotes sprouting angiogenesis in retinal neovascularization, mediated via the activation of both tip cells and microglia at least partially.
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