['To determine if cannabinoid receptor 2 (CB2) plays a role in atherosclerosis, we investigated the effects of systemic CB2 gene deletion on hyperlipidemia-induced atherogenesis in low density lipoprotein receptor-deficient (Ldlr(-/-)) mice.', 'Ldlr(-/-) and CB2/Ldlr double knockout (CB2(-/-)Ldlr(-/-)) mice were fed an atherogenic diet for 8 and 12 weeks. Morphometric analysis revealed no significant difference between the atherosclerotic lesion area in the proximal aortas of Ldlr(-/-) and CB2(-/-)Ldlr(-/-) mice after 8 or 12 weeks on the atherogenic diet. The macrophage and smooth muscle cell (SMC) content, as revealed by immunohistochemical staining, did not differ significantly between Ldlr(-/-) and CB2(-/-)Ldlr(-/-) lesions after 8 weeks. However, after 12 weeks, CB2(-/-)Ldlr(-/-) lesions displayed greater macrophage content (86.6 ± 4.1 versus 75.2 ± 7.5%, P<0.05) and SMC content (11.1 ± 5.1 versus 4.2 ± 2.4%, P<0.05) compared to controls. Lesional apoptosis, as determined by in situ TUNEL analysis, was reduced ~50% in CB2(-/-)Ldlr(-/-) lesions after 12 weeks. CB2(-/-)Ldlr(-/-) lesions displayed significantly reduced collagen content and increased elastin fiber fragmentation after 12 weeks, which was associated with an ~57% increase in matrix metalloproteinase 9 (MMP) levels. In vitro, CB2(-/-) macrophages secreted ~1.8-fold more MMP9 activity than CB2(+/+) macrophages.'] Does cannabinoid receptor type 2 ( CB2 ) deficiency alter atherosclerotic lesion formation in hyperlipidemic Ldlr-null mice?