Abstract
Insulin-like growth factor (IGF)-I is a pleiotropic hormone that regulates vascular smooth muscle cell (VSMC) migration, proliferation, apoptosis, and differentiation. These actions are mediated by the IGF-I receptor. How activation of the same receptor by the same ligand leads to these diverse cellular responses is not well understood. Here we describe a novel mechanism specifying VSMC responses to IGF-I stimulation, distinctive for the pivotal roles of local IGF-binding proteins (IGFBPs). The role of local IGFBPs was indicated by comparing the activities of IGF-I and des-1-3-IGF-I, an IGF-I analog with reduced binding affinity to IGFBPs. Compared with IGF-I, des-1-3-IGF-I was more potent in stimulating DNA synthesis but much less potent in inducing directed migration of VSMCs. When the effects of individual IGFBPs were tested, IGFBP-2 and IGFBP-4 were found to inhibit IGF-I-stimulated DNA synthesis and migration. IGFBP-5 had an inhibitory effect on IGF-I-stimulated DNA synthesis, but it strongly potentiated IGF-I-induced VSMC migration. By using a non-IGF-binding IGFBP-5 mutant and an IGF-I-neutralizing antibody, it was demonstrated that IGFBP-5 also stimulates VSMC migration in an IGF-independent manner. This effect of IGFBP-5 was inhibited by soluble heparin and by treating cells with heparinase. Mutation of the heparin-binding motif of IGFBP-5 reduced its migration promoting activity. These findings suggest that local IGFBPs are important determinants of cellular responses to IGF-I stimulation, and a key player in this paradigm is IGFBP-5. IGFBP-5 not only modulates IGF-I actions, but it also stimulates cell migration by interacting with cell-surface heparan sulfate proteoglycans.
Highlights
Insulin-like growth factors (IGFs),1 including IGF-I and IGFII, are peptide growth factors structurally related to proinsulin
The Local Repertoire of IGFbinding proteins (IGFBPs) Is Critical in Determining Whether vascular smooth muscle cells (VSMCs) Migrate or Proliferate in Response to IGF-I Stimulation—To test the hypothesis that the local repertoire of IGFBPs may affect the cellular responses to IGF-I stimulation, we examined the effects of IGF-I and des-1–3-IGF-I on VSMC growth and migration
Addition of IGFBP-5 stimulated VSMC migration in a dose-dependent fashion with or without IGF-I. These results suggest that IGFBP-2 and IGFBP-4 act as inhibitors of IGF-I actions, whereas IGFBP-5 potentiates IGFinduced VSMC migration
Summary
Insulin-like growth factors (IGFs), including IGF-I and IGFII, are peptide growth factors structurally related to proinsulin. IGFs have been shown to regulate VSMC differentiation, glucose uptake, protein synthesis, and contractility [10] These diverse actions of IGFs are mediated through the IGF-I receptor (IGFIR) and its downstream signaling transducers, including mitogen-activated protein kinases, phosphatidylinositol 3-kinase, and protein kinase C [7, 8, 11,12,13]. Bovine, rat, and mouse indicate that mammalian VSMCs secrete IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 (6, 9, 18 –23) These IGFBPs, when added exogenously to cultured VSMCs in combination with IGF-I, can either inhibit or potentiate IGF-I-induced DNA synthesis and migration (6, 19, 21, 24 –26). The goals of this study were to determine whether IGFBPs regulate the chemotactic and mitogenic responses of VSMCs to IGF stimulation, and to elucidate the individual role(s) and underlying mechanisms of local IGFBPs in regulating VSMC migration and proliferation
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