Under usual conditions, the role of IGF-I in vascular cell types is to maintain cellular protein synthesis and cell size, and even excess IGF-I does not stimulate proliferation. In pathophysiologic states, such as hyperglycemia, smooth muscle cells (SMC) de-differentiate and change their responsiveness to IGF-I. During hyperglycemia IGF-I stimulates both SMC migration and proliferation. Our laboratory has investigated the molecular mechanism by which this change is mediated. Following hyperglycemia SMC secrete increased concentrations of thrombospondin, vitronectin and osteopontin, ligands for the integrin αVβ3. Activation of αVβ3 stimulates recruitment of a tyrosine phosphatase, SHP-2. Exposure of SMC to IGF-I results in phosphorylation of the transmembrane protein, SHPS-1, which provides a docking site for αVβ3-associated SHP-2. After IGF-I stimulation SHP-2 associates with Src kinase, which associates with the signaling protein Shc. Src phosphorylates Shc, resulting in activation of MAP kinases, which are necessary both for stimulation of cell proliferation and migration. Blocking activation of αVβ3 results in an inability of IGF-I to stimulate Shc phosphorylation. Under conditions of normoglycemia, there are insufficient αVβ3 ligands to recruit SHP-2, and no increase in Shc phosphorylation can be demonstrated in SMC. In contrast, if αVβ3 ligands are added to cells in normal glucose, the signaling events that are necessary for Shc phosphorylation can be reconstituted. Therefore when SMC are exposed to normal glucose they are protected from excessive stimulation of mitogenesis by IGF-I. With hyperglycemia there is a marked increased in αVβ3 ligands and Shc phosphorylation in response to IGF-I is sustained. These findings indicate that in SMC hyperglycemic stress may leads to altered IGF-I signaling, which allows the cells to undergo a mitogenic response, and which may contribute to the development of atherosclerosis
