Vascular cell adhesion molecule-1 up-regulation and phenotypic modulation of vascular smooth muscle cells predate mononuclear infiltration in transplant arteriopathy

Objective: Expression of embryonic myosin heavy chain isoforms and vascular cell adhesion molecule-1 by neointimal vascular smooth muscle cells are in dependent indicators of atherosclerotic plaque development in both human be ings and experimental animal models. We examined the chronologic change in smooth muscle cell myosin heavy chain isoforms, vascular cell adhesion mole cule-1 expression, and mononuclear cell infiltration in a carotid arterial transplant model to ascertain whether similar phenotypic changes would occu r in transplant arteriopathy. Methods: Transplanted rabbit carotid arteries were examined at 7, 14, 21, a nd 35 days (n = 5, 7, 6, and 5, respectively). Lesion progression and the p revalence of smooth muscle cell myosin heavy chain isoforms, T-lymphocytes, macrophages, and vascular cell adhesion molecule-1 expression were evaluat ed immunohistochemically by computerized image analysis. Results: In this carotid arterial transplant model, the intima/media area r atio increased significantly by 35 days (P =.01) as cell density decreased (P =.01), suggesting extracellular matrix elaboration. Intimal smooth muscl e cells expressing embryonic phenotypes were seen as early as 7 days, a phe notypic change that predated mononuclear cell infiltration of the graft by at least 7 days. By 35 days, up to 70% of intimal smooth muscle cells expre ssed the embryonic phenotype, coinciding with the transition from inflammat ory to chronic lesions. Although, in early lesions, vascular cell adhesion molecule-1 was identified on luminal endothelium overlying mononuclear infi ltrates, in advanced lesions vascular cell adhesion molecule-1 was identifi ed primarily on intimal vascular smooth muscle cells. Conclusions: Overall, these vascular smooth muscle cell changes marls impor tant early events in transplant arteriopathy that may not be ameliorated by immunosuppressive regimens in routine use.