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Roles of Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase Pathways in Stimulation of Vascular Smooth Muscle Cell Migration and Deoxyriboncleic Acid Synthesis by Insulin-Like Growth Factor-I¹

Division of Endocrinology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7170

Address all correspondence and requests for reprints to: David R. Clemmons Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina 27599-7170. E-mail: dpm{at}med.unc.edu

Insulin-like growth factor-I (IGF-I) is a potent stimulator of vascular smooth muscle cell (SMC) migration, a process that contributes to the accumulation of SMC within atherosclerotic lesions. Our previous studies have shown that IGF-I increases the affinity of the Vß3 integrin toward ligands and that occupancy of this integrin is indispensable for IGF-I to stimulate cell migration. In this study, the role of phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinase (MAPK) pathways in IGF-I induced cell motility and integrin activation was studied using porcine aortic smooth muscle cells (pSMC). Two structurally different inhibitors of PI 3-kinase decreased IGF-I-stimulated pSMC migration in a dose-dependent manner. The IC₅₀ of wortmannin for inhibiting migration was 10 nM, and that of LY294002 was 0.3 µM. These inhibitors also suppressed IGF-I-induced phosphorylation of protein kinase B PKB/Akt at Ser⁴³⁷ using concentrations that also inhibited cell motility. PD98059, an inhibitor of the MAPK pathway, was somewhat less potent than PI 3-kinase inhibitors in blocking cell migration that had been stimulated by IGF-I. When IGF-I increased migration of pSMC 2.1-fold above control, 100 nM wortmannin inhibited this response by 79%, 1 µM LY294002 inhibited it by 58%, and 50 µM PD98059 caused a 34% reduction. In comparison, 100 nM wortmannin inhibited IGF-I stimulated DNA synthesis by 57%, 1 µM LY294002 inhibited it by 59%, whereas 50 µM PD98059 suppressed it completely. Thus, activation of PI 3-kinase plays the major role in IGF-I-stimulated migration and proliferation of pSMC. While the activation of the MAPK pathway seems to be necessary for stimulation of mitogenesis by IGF-I, the contribution of this pathway in IGF-I-induced cell migration is limited in pSMC. Interestingly, neither PI 3-kinase inhibitors nor PD98059 blocked the increase in Vß3 integrin affinity that followed IGF-I treatment. Therefore, although both the PI 3-kinase and MAPK pathways were used by IGF-I to increase migration of pSMC, Vß3 integrin activation did not depend on either PI 3-kinase or MAPK activation, suggesting the possible importance of some other signal transduction pathway to account for its full actions on pSMC.

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