Vascular pathologies are known to be associated with
age-related macular degeneration. Recently,
age-related macular degeneration was associated with a single-
nucleotide substitution of the
complement factor H (CFH) gene, part of the alternative pathway of the
complement system, a critical
element in the innate immune response. Such polymorphisms are found in more than 50% of cases of
age-related macular degeneration. Here we show that the absence of CFH causes an autoimmune response that targets the vascular endothelium of both the inner and outer
retinal vascular networks. In CFH-knockout (cfh(-/-)) mice, C3 and C3b, key components of the
complement system, are progressively deposited on retinal vessels, which subsequently become restricted and wither, resulting in a reduction of
retinal blood supply. This result leads to increased
oxygen stress. While such effects are not systemic, these structural changes are mirrored in functional changes with a substantial decline in
retinal blood flow dynamics. When the system is challenged functionally by
laser-induced
choroidal neovascularization,
fluorescein leakage was significantly smaller in cfh(-/-) mice compared with controls, likely due to reduced
retinal perfusion. These data reveal that in both the presence and absence of exogenous challenge to the innate immune system, CFH is required to maintain normal levels of
retinal perfusion. It is likely that C3 and C3b accumulation in the aged CFH-deficient retina is associated with
complement-mediated
retinal endothelium destruction.