The blood vessels of aging animals are characterized by a number of histological changes, including an increase in the number of vascular smoot muscle cells (VSMCs) and monocytes in the intima. These changes are likely to contribute to the increased occurrence and severity of vascular disease that is associated with aging. Advanced glycation endproducts of proteins (AGE) accumulate in the plasma and in tissues with age and at an accelerate rate in diabetes. These products have been shown to stimulate the secretio of chemoattractants and expression of cell adhesion molecules by circulatin leukocytes and, in the case of diabetes, have been linked to the developmen of vascular complications. A receptor for AGE (RAGE) has been identified and cloned. Using an antibody for this receptor, we have shown that RAGE i expressed in the vessel wall by the endothelium and by intimal vascular smooth muscle cells, indicating that they are likely targets of AGEs. Incubation of quiescent VSMCs with AGE-albumin induces the expression of monocyte chemoattractant protein-1 (MCP-1) mRNA over 10-fold, whereas nativ albumin was without effect. These changes in MCP-1 mRNA expression were inhibited by pre-incubation with the RAGE antibody, which blocks ligand binding, and with the antioxidant, probucol. VSMCs exposed to AGE-albumin also secreted a chemoattractant into conditioned media which stimulated VSM migration 5-fold (p, 0.01). This activity was blocked by anti-PDGF IgG (78%, p, 0.05), but not by nonimmune IgG. RAGE expression was dramatically upregulated following vessel injury with the increase in expression confine to the developing neointima. This difference in RAGE expression between medial and neointimal cells persisted in culture and is likely responsible for the exaggerated AGE-responsiveness of neointimal cells. These studies demonstrate that VSMCs are targets for AGE and that the consequences of thi interaction could result in increased VSMC migration and monocyte infiltration, an early event in atherogenesis. Furthermore, the upregulation of RAGE expression in young, non-diabetic animals in which AGE are not detectable suggests that receptor activation may also occur through additional unknown ligands and that activation of RAGE may play a role in all forms of vascular injury and disease.
