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

Abstract

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 Ϫ/Ϫ 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 ␣-smooth muscle actin promoter, after backcrossing to the Apoe Ϫ/Ϫ background (SMP8/Apoe Ϫ/Ϫ ). Compared with Apoe Ϫ/Ϫ mice, these SMP8/Apoe Ϫ/Ϫ 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 Ϫ/Ϫ mice displayed several features of plaque stability, including increased fibrous cap area, ␣-smooth muscle actin-positive SMC and collagen content, and reduced necrotic cores. Traditionally, the role of growth factors in atherosclerosis has been thought to be permissive and to promote neointima formation. 6 -8 Insulin-like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that exerts pleiotropic effects on cells involved in atherogenesis. 9 Notably, it has mitogenic and antiapoptotic actions on endothelial cells and VSMC and stimulates VSMC migration. 10 Consistent with the role of IGF-1 as a VSMC mitogen, most [11][12][13][14] but not all 15 studies using inhibitors have demonstrated that reduced VSMC IGF-1 signaling correlates with decreased neointimal responses to mechanical arterial injury. Furthermore, targeted overexpression of IGF-1 in SMC increases neointimal formation. 16 However, although mechanical arterial injury models provide much information about the restenotic process, they have significant limitations when addressing mechanisms of atherogenesis, and the role of VSMC IGF-1 in the latter process remains unclear. Conclusion-TheseWe have previously shown that oxidized low-density lipoprotein downregulates IGF-1 and IGF-1 receptor expression in VSMC 17,18 and that expression of IGF-1 and IGF-1 receptor is reduced in areas of advanced human plaque staining positive for oxidized low-density lipoprotein. 19 These findings suggest that decreased IGF-1 activity could contribute to the atherosclerotic process and notably to depletion of VSMC in advanced unstable plaque. Similar findings have been reported in cultured plaque-derived VSMC. 20 We recently reported that infusion of recombinant human IGF-1 into Apoe-deficient mice on a Western diet for ...

Insulin-like Growth Factor-1 Increases Synthesis of Collagen Type I via Induction of the mRNA-binding Protein LARP6 Expression and Binding to the 5′ Stem-loop of COL1a1 and COL1a2 mRNA

“…IGF-1 infusion and SMCspecific IGF-1 overexpression increases features of plaque stability including up-regulation of plaque collagen levels (19,21), however the mechanism mediating this effect has not been identified. Here we report that IGF-1 increases expression of LARP6 in vascular SMCs resulting in increased binding of LARP6 to the 5ЈSL of Col1a1 and Col1a2 mRNAs and enhanced synthesis of collagen type I.…”

“…Our previous studies in vivo have shown that IGF-1 infusion in Apoe Ϫ/Ϫ mice significantly reduced oxidative stress and atherosclerosis, and increased plaque collagen (19,20). SMC-specific IGF-1 overexpression did not change atherosclerotic plaque burden, but did increase collagen content in atherosclerotic plaque together with other features of plaque stability (21). In the current study, we investigate the mechanisms by which IGF-1 increases collagen type I in vascular smooth muscle.…”

Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice

“…In vivo, transgenic mice with an overexpression of IGF-1 in SMCs develop hyperplasia and increased SMC layer thickness in several organs without a change in plasma IGF-1 levels, implicating a paracrine effect (21). Chronic expression of IGF-1 within the vessel wall is also associated with increased arterial contractility (22)(23)(24), and direct stimulation of aortic SMCs with IGF-1 in vitro increases the expression of SMC differentiation markers, a-SMA, calponin, and SM22a (25). In addition, IGF-1 has the ability to stimulate elastin in vascular SMCs (26), and increased IGF-1 expression has been associated with remodeling in sheep models of neonatal PH (27,28).…”

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

“…Interestingly, developmental IGF-1 deficiency is also associated with decreased collagen expression in the cardiovascular system of Ames dwarf mice (Helms et al 2010). Future studies are evidently needed to experimentally dissect the IGF-regulated pathways regulating extracellular matrix homeostasis and vascular remodeling (Bruel and Oxlund 2002;Shai et al 2010;Ungvari and Csiszar 2012) in the models used.…”