Smooth muscle cell-specific insulin-like growth factor-1 overexpression in Apoe-/- mice does not alter atherosclerotic plaque burden but increases features of plaque stability

Shaw-Yung Shai, Sergiy Sukhanov, Yusuke Higashi, Charlotte Vaughn, James Kelly, Patrice Delafontaine
Arteriosclerosis, Thrombosis, and Vascular Biology 2010, 30 (10): 1916-24

OBJECTIVE: Growth factors may play a permissive role in atherosclerosis initiation and progression, in part via their promotion of vascular smooth muscle cell (VSMC) accumulation in plaques. However, unstable human plaques often have a relative paucity of VSMC, which has been suggested to contribute to plaque rupture and erosion and to clinical events. Insulin-like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that is a mitogen for VSMC, but when infused into Apoe(-/-) mice it paradoxically reduces atherosclerosis burden.

METHODS AND RESULTS: To determine the effect of stimulation of VSMC growth on atherosclerotic plaque development and to understand mechanisms of IGF-1's atheroprotective effect, we assessed atherosclerotic plaques in mice overexpressing IGF-1 in smooth muscle cells (SMC) under the control of the α-smooth muscle actin promoter, after backcrossing to the Apoe(-/-) background (SMP8/Apoe(-/-)). Compared with Apoe(-/-) mice, these SMP8/Apoe(-/-) mice developed a comparable plaque burden after 12 weeks on a Western diet, suggesting that the ability of increased circulating IGF-1 to reduce plaque burden was mediated in large part via non-SMC target cells. However, advanced plaques in SMP8/Apoe(-/-) mice displayed several features of plaque stability, including increased fibrous cap area, α-smooth muscle actin-positive SMC and collagen content, and reduced necrotic cores.

CONCLUSIONS: These findings indicate that stimulation of VSMC IGF-1 signaling does not alter total atherosclerotic plaque burden and may improve atherosclerotic plaque stability.

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