The blood vessels of aging animals are characterized by a number of histological changes, including an increase in the number of vascular smooth 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 accelerated rate in diabetes and in advanced atherosclerotic lesions. A receptor for AGE (RAGE) has been identified and cloned and we have previously shown that RAGE is expressed in the vessel wall by the endothelium and by intimal vascular smooth muscle cells, indicating that they are likely targets of AGEs. RAGE expression is also dramatically upregulated following vessel injury with the increase in expression confined to the developing neointima. Incubation of quiescent intimal VSMCs and endothelial cells with AGE-albumin leads to a receptor-dependent intracellular oxidant stress and induces NF-kB activity. In VSMCs, AGEs also induce expression of monocyte chemoattractant protein-1 (MCP-1) and PDGF B chain, which are leukocyte and VSMC chemoattractants, respectively. These changes in transcription factor and gene expression are inhibited by soluble RAGE, which prevents AGE binding to RAGE, and by the antioxidants, probucol and N-acetylcysteine. In intimal VSMCs but not in endothelial cells, crosslinking of RAGE with affinity purified antibodies to the receptor also results in activation of NF-kB and increased MCP-1 and PDGF expression. Transfection of medial VSMCs which express low levels of the endogenous receptor with wild type and in vitro mutated RAGEs is currently being conducted to identify signal transduction pathways for AGE-mediated changes in gene expression in the cell. Overall, these studies demonstrate that VSMCs are targets for AGE and that the consequences of this interaction could result in increased VSMC migration and monocyte infiltration, a likely prelesional event in atherogenesis.
