LAUSR

Objective— IGF-1 (insulin-like growth factor 1) is a major autocrine/paracrine growth factor, which promotes cell proliferation, migration, and survival. We have shown previously that IGF-1 reduced atherosclerosis and promoted features of stable atherosclerotic plaque in Apoe−/− mice—an animal model of atherosclerosis. The aim of this study was to assess effects of smooth muscle cell (SMC) IGF-1 signaling on the atherosclerotic plaque. Approach and Results— We generated Apoe−/− mice with IGF1R (IGF-1 receptor) deficiency in SMC and fibroblasts (SM22&agr; [smooth muscle protein 22 &agr;]-CreKI/IGF1R-flox mice). IGF1R was decreased in the aorta and adventitia of SM22&agr;-CreKI/IGF1R-flox mice and also in aortic SMC, embryonic, skin, and lung fibroblasts isolated from SM22&agr;-CreKI/IGF1R-flox mice. IGF1R deficiency downregulated collagen mRNA-binding protein LARP6 (La ribonucleoprotein domain family, member 6) and vascular collagen, and mice exhibited growth retardation. The high-fat diet–fed SM22&agr;-CreKI/IGF1R-flox mice had increased atherosclerotic burden and inflammatory responses. &agr;-SMA (&agr;-smooth muscle actin)–positive plaque cells had reduced proliferation and elevated apoptosis. SMC/fibroblast-targeted decline in IGF-1 signaling decreased atherosclerotic plaque SMC, markedly depleted collagen, reduced plaque fibrous cap, and increased plaque necrotic cores. Aortic SMC isolated from SM22&agr;-CreKI/IGF1R-flox mice had decreased cell proliferation, migration, increased sensitivity to apoptosis, and these effects were associated with disruption of IGF-1–induced Akt signaling. Conclusions— IGF-1 signaling in SMC and in fibroblast is a critical determinant of normal vascular wall development and atheroprotection.