Abdominal aortic aneurysms (AAAs) are characterized by structural deterioration of the aortic wall leading to progressive aortic dilatation and eventual rupture. The histopathological changes in AAAs are particularly evident within the elastic media, which is normally dominated by vascular smooth muscle cells (SMCs). To determine whether a decrease in vascular SMCs contributes to medial degeneration, we measured SMC density in 21 normal and pathological human abdominal aortic tissue specimens using immunohistochemistry for alpha-SMC actin and direct cell counts (medial SMCs per high-power field (HPF)). Medial SMC density was not significantly different between normal aorta (n = 5; 199.5 +/- 14.9 SMCs/HPF) and atherosclerotic occlusive disease (n = 6; 176.4 +/- 13.9 SMCs/HPF), but it was reduced by 74% in AAA (n = 10; 50.9 +/- 6.1 SMCs/HPF; P < 0.01 versus normal aorta). Light and electron microscopy revealed no evidence of overt cellular necrosis, but SMCs in AAAs exhibited ultrastructural changes consistent with apoptosis. Using in situ end-labeling (ISEL) of fragmented DNA to detect apoptotic cells, up to 30% of aortic wall cells were ISEL positive in AAAs. By double-labeling techniques, many of these cells were alpha-actin-positive SMCs distributed throughout the degenerative media. In contrast, ISEL-positive cells were observed only within the intimal plaque in atherosclerotic occlusive disease. The amount of p53 protein detected by immunoblotting was increased nearly fourfold in AAA compared with normal aorta and atherosclerotic occlusive disease (P < 0.01), and immunoreactive p53 was localized to lymphocytes and residual SMCs in the aneurysm wall. Using reverse transcription polymerase chain reaction assays a substantial amount of p53 mRNA expression was observed in AAAs. These results demonstrate that medial SMC density is significantly decreased in human AAA tissues associated with evidence of SMC apoptosis and increased production of p53, a potential mediator of cell cycle arrest and programmed cell death. Given the role that SMCs normally play in maintaining medial architecture and in arterial wall matrix remodeling, the induction of SMC apoptosis likely makes an important contribution to the evolution of aneurysm degeneration.