title: Macrophage activation associated with chronic murine cytomegalovirus infection results in more severe experimental choroidal neovascularization.
abstract: 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.
authors.affiliation: Duke University Eye Center, Duke Center for Macular Diseases, Department of Ophthalmology, Duke University, Durham, North Carolina, United States of America.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Cousins
authors.forename: Diego G
authors.initials: DG
authors.lastname: Espinosa-Heidmann
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Miller
authors.forename: Simone
authors.initials: S
authors.lastname: Pereira-Simon
authors.forename: Eleut P
authors.initials: EP
authors.lastname: Hernandez
authors.forename: Hsin
authors.initials: H
authors.lastname: Chien
authors.forename: Courtney
authors.initials: C
authors.lastname: Meier-Jewett
authors.forename: Richard D
authors.initials: RD
authors.lastname: Dix
mesh_terms: D000818:Animals; D002829:Choroid / Q000098:blood supply* / Q000473:pathology; D020256:Choroidal Neovascularization / Q000209:etiology* / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D006566:Herpesviridae Infections / Q000150:complications / Q000276:immunology*; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A