Background— The influence of complement activation on atherosclerosis is not well understood. The purpose of this study was to examine the effects of C3 deficiency on the extent and phenotype of atherosclerosis.

Methods and Results— Aortic atherosclerosis was analyzed in low-density lipoprotein receptor (ldlr)/C3-deficient mice (ldlr^−/−C3^−/−) and ldlr^−/−C3^+/− littermate control mice after 15 weeks on a 1.25% (wt/wt) cholesterol diet. Serum lipoprotein profiles and immunoglobulin levels were not significantly different between the 2 experimental groups. The lipid-positive en face lesional area in thoracic and abdominal aorta was greater in C3-deficient mice than in control mice (3.9% versus 2.1%, median, P=0.0076). Similarly, the lipid-positive area in aortic arch sections was greater in C3-deficient mice than in controls (0.04 mm² versus 0.02 mm², median, P=0.0089). Analysis of aortic arch sections showed greater lesional macrophage content in C3-deficient versus control mice (8.24±1.36% versus 5.9±1.63% intimal area, mean±SEM, P=0.003), less smooth muscle cell content in C3-deficient versus control mice (0.06±0.05% versus 0.92±0.32% intimal area, mean±SEM, P<0.0001), and less collagen content in C3-deficient versus control mice (0.52±1.26% versus 11±10.43% intimal area, mean±SEM, P=0.008).

Conclusions— The maturation of atherosclerotic lesions beyond the foam cell stage is strongly dependent on an intact complement system.