Macrophage activation associated with chronic murine cytomegalovirus infection results in more severe experimental choroidal neovascularization

The neovascular (wet) form of age-related macular degeneration (amd) leads to vision loss due to choroidal neovascularization (cnv). since macrophages are important in cnv development,and cytomegalovirus (cmv)-specific igg serum titers in patients with wet amd are elevated,we hypothesized that chronic cmv infection contributes to wet amd,possibly by pro-angiogenic macrophage activation. this hypothesis was tested using an established mouse model of experimental cnv. at 6 days,6 weeks,or 12 weeks after infection with murine cmv (mcmv),laser-induced cnv was performed,and cnv severity was determined 4 weeks later by analysis of choroidal flatmounts. although all mcmv-infected mice exhibited more severe cnv when compared with control mice,the most severe cnv developed in mice with chronic infection,a time when mcmv-specific gene sequences could not be detected within choroidal tissues. splenic macrophages collected from mice with chronic mcmv infection,however,expressed significantly greater levels of tnf-α,cox-2,mmp-9,and,most significantly,vegf transcripts by quantitative rt-pcr assay when compared to splenic macrophages from control mice. direct mcmv infection of monolayers of ic-21 mouse macrophages confirmed significant stimulation of vegf mrna and vegf protein as determined by quantitative rt-pcr assay,elisa,and immunostaining. stimulation of vegf production in vivo and in vitro was sensitive to the antiviral ganciclovir. these studies suggest that chronic cmv infection may serve as a heretofore unrecognized risk factor in the pathogenesis of wet amd. one mechanism by which chronic cmv infection might promote increased cnv severity is via stimulation of macrophages to make pro-angiogenic factors (vegf),an outcome that requires active virus replication. © 2012 cousins et al.