Although a metabolic role for endothelium in toxic injury has been well established, a similar role has not been as thoroughly explored for the vascular media. In this study two forms of vascular medial involvement in toxic injury are examined. Early atherosclerotic plaques are studied by immunohistochemistry for an a class glutathione-S-transferase (GST) isozyme known as hGSTA4-4, which has preferential metabolic activity for a, ss -unsaturated aldehydes derived from lipid peroxidation, especially 4-hydroxy-2-nonenal. Findings in human plaque indicate that hGST A4-4 is highly upregulated in vascular smooth muscle cells (VSMCs) within the plaque and in the medial VSMCs underlying plaque. Endothelial cells, while not expressing hGST A4-4 distant from plaques, were found to express the isozyme in cytoplasm overlying plaque. In a series of second experiments, we illustrate a developmental model of dissecting aortic aneurysm (DAA) obtained by administering semicarbazide, an inhibitor of the little-studied VSMC enzyme semicarbazide-sensitive amine oxidase (SSAO), to pregnant rats during the last trimester of development. Newborn rats consistently developed DAA which is characterized by splitting of media of ascending thoracic aorta and extensive blood collections surrounding the vessel. These experimental examples emphasize the potential role of the media in toxic insults to blood vessels. Also, the potential importance of toxic injury to developing blood vessels by in utero exposure to xenobiotic substances is illustrated.