Fibronectin glycation increases IGF-I induced proliferation of human aortic smooth muscle cells

Both type I and type II diabetes are powerful and independent risk factors for coronary artery disease, stroke, and peripheral arterial disease [1,2]. Prolonged exposure to hyperglycemia is recognized as the primary casual factor in the pathogenesis of diabetic complications [3,4]. Hyperglycemia induces a large number of alterations in vascular tissue that potentially promote accelerated atherosclerosis. Glycation of proteins is an important biochemical mechanism by which glucose mediates tissue damage, leading to the generation of advanced glycation endproducts (AGEs) and modifying the structure and function of several proteins, such as those which comprise extracellular matrixes [5]. It has been demonstrated that AGE formation alters some functional properties of collagen [6], vitronectin [7], laminin [8], and fibronectin (FN) [9], affecting their self-assembly and their binding to each other. AGEs can also induce synthesis and secretion of cytokines and growth factors after binding to AGE receptors (RAGE) in different cell types [7]. Monocytes exposed to AGE-modified matrix release tumor necrosis factor-α (TNF-α) [10], platelet-derived growth factor (PDGF) [11] and insulin-like growth factor-I (IGF-I) [12]. In vascular smooth muscle cells (SMC) AGE-RAGE interaction has been shown to activate cell signalling pathways linked to expression of inflammatory and prothrombotic genes, such as ERK1/ERK2 kinases and NF-kB [13].The SMC, which constitute the medial layer of arteries, are normally in a differentiated contractile phenotype, but during the development of atherosclerotic lesions, a subpopulation of SMC is converted to a synthetic phenotype that is able to migrate and proliferate. Extracellular matrix proteins actively participate in this process, affecting SMC phenotype and modulating the cellular response to growth-regulatory molecules [14]. FN, which is found in increased amounts in early atherosclerotic plaques [15,16], can interact with cell surface receptor