Age‐related differences in insulin‐like growth factor‐1 receptor signaling regulates Akt/FOXO3a and ERK/Fos pathways in vascular smooth muscle cells

Abstract

Advanced age is a major risk factor for atherosclerosis, but how aging per se influences pathogenesis is not clear. Insulin‐like growth factor‐1 receptor (IGF‐1R) promotes aortic vascular smooth muscle cell (VSMC) growth, migration, and extracellular matrix formation, but how IGF‐1R signaling changes with age in VSMC is not known. We previously found age‐related differences in the activation of Akt/FOXO3a and ERK1/2 pathways in VSMC, but the upstream signaling remains unclear. Using explanted VSMC from Fischer 344/Brown Norway F1 hybrid rats shown to display age‐related vascular pathology similar to humans, we compared IGF‐1R expression in early passages of VSMC and found a constitutive activation of IGF‐1R in VSMC from old compared to young rats, including IGF‐1R expression and its tyrosine kinase activity. The link between IGF‐1R activation and the Akt/FOXO3a and ERK pathways was confirmed through the induction of IGF‐1R with IGF‐1 in young cells and attenuation of IGF‐1R with an inhibitor in old cells. The effects of three kinase inhibitors: AG1024, LY294002, and TCN, were compared in VSMC from old rats to differentiate IGF‐1R from other upstream signaling that could also regulate the Akt/FOXO and ERK pathways. Genes for p27kip‐1, catalase and MnSOD, which play important roles in the control of cell cycle arrest and stress resistance, were found to be FOXO3a‐targets based on FOXO3a‐siRNA treatment. Furthermore, IGF‐1R signaling modulated these genes through activation of the Akt/FOXO3a pathway. Therefore, activation of IGF‐1R signaling influences VSMC function in old rats and may contribute to the increased risk for atherosclerosis. J. Cell. Physiol. 217: 377–387, 2008.