Abstract-The vascular insulin-like growth factor (IGF)-1 system includes the IGFs, the IGF-1 receptor (IGF-1R), and multiple binding proteins. This growth factor system exerts multiple physiologic effects on the vasculature through both endocrine and autocrine/paracrine mechanisms. The effects of IGF-1 are mediated principally through the IGF-1R but are modulated by complex interactions with multiple IGF binding proteins that themselves are regulated by phosphorylation, proteolysis, polymerization, and cell or matrix association. During the last decade, a significant body of evidence has accumulated, indicating that expression of the components of the IGF system are regulated by multiple factors, including growth factors, cytokines, lipoproteins, reactive oxygen species, and hemodynamic forces. In addition, cross-talk between the IGF system and other growth factors and integrin receptors has been demonstrated. There is accumulating evidence of a role for IGF-1 in multiple vascular pathologies, including atherosclerosis, hypertension, restenosis, angiogenesis, and diabetic vascular disease. This review will discuss the regulation of expression of IGF-1, IGF-1R, and IGF binding proteins in the vasculature and summarize evidence implicating involvement of this system in vascular diseases.

Objective-Whereas growth factors, via their ability to stimulate vascular smooth muscle cell (VSMC) proliferation and migration, have been thought to play a permissive role in atherosclerosis initiation and progression, the role of insulin-like growth factor-1 (IGF-1) is unknown. Here we report for the first time that IGF-1 infusion decreased atherosclerotic plaque progression in ApoE-deficient mice on a Western diet. Methods and Results-ApoE-null mice (8 weeks) were infused with vehicle or recombinant human IGF-1 and fed a high-fat diet for 12 weeks. Analysis of aortic sinuses revealed that IGF-1 infusion decreased atherosclerotic plaque progression and macrophage infiltration into lesions. Furthermore, IGF-1 decreased vascular expression of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-␣, reduced aortic superoxide formation and urinary 8-isoprostane levels, and increased aortic pAkt and eNOS expression and circulating endothelial progenitor cells, consistent with an antiinflammatory, antioxidant, and prorepair effect on the vasculature. Conclusions-Our data indicate that an increase in circulating IGF-1 reduces vascular inflammatory responses, systemic and vascular oxidant stress and decreases atherosclerotic plaque progression. These findings have major implications for the treatment of atherosclerosis. Key words: insulin-like growth factor Ⅲ atherosclerosis Ⅲ apolipoprotein E Ⅲ inflammatory response Ⅲ oxidative stress A therosclerosis is the principal underlying cause of most cardiovascular disease-related deaths, the leading cause of mortality in the USA. 1 Long considered to result from progressive vascular lipid accumulation, atherosclerosis is now recognized as a chronic inflammatory disease, 2-5 in which oxidative stress plays a key initiating role. Thus, multiple oxidative stimuli including oxidation of low-density lipoprotein (LDL) in the subendothelial space can result in endothelial cell adhesion molecule expression, monocyte and T cell recruitment, and macrophage lipid accumulation and foam cell formation. 6 Growth factors, cytokines, chemokines, and proteases modulate many steps in the atherosclerotic process including the migration and proliferation of smooth muscle cells. Furthermore, vascular and extravascular progenitor cells contribute to atherogenesis, and these include circulating endothelial progenitor cells (EPCs) that are likely part of a vascular repair system. 7 Insulin-like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that is the primary mediator of the effect of growth hormone (GH) on developmental growth. 8 IGF-1 is expressed in vascular cells 9 and in monocyte/macrophages, 10,11 but its role in atherogenesis is unknown. IGF-1 is a mitogen for endothelial cells 12 and vascular smooth muscle cells, 13 and can potentiate endothelial cell TNF-␣-induced c-Jun and NF-B activation. 14 Furthermore, IGF-1 has potent survival effects on vascular cells and prevents oxidized LDL-induced apoptosis of vascular smooth muscle cells. 15 We ha...