Insulin affects vascular smooth muscle cell phenotype and migration via distinct signaling pathways.
Insulin maintains vascular smooth muscle cell (VSMC) quiescence yet can also promote VSMC migration. The mechanisms by which insulin exerts these contrasting effects were examined using alpha-smooth muscle actin (alpha-SMA) as a marker of VSMC phenotype because alpha-SMA is highly expressed in quiescent but not migratory VSMC. Insulin alone maintained VSMC quiescence and modestly stimulated VSMC migration. Wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, decreased insulin-stimulated expression of alpha-SMA mRNA by 26% and protein by 48% but had no effect on VSMC migration. PD98059, a mitogen-activated protein kinase (MAPK) kinase inhibitor, decreased insulin-induced VSMC migration by 52% but did not affect alpha-SMA levels. Platelet-derived growth factor (PDGF) promoted dedifferentiation of VSMC, and insulin counteracted this effect. Furthermore, insulin increased alpha-SMA mRNA and protein levels to 111 and 118%, respectively, after PDGF-induced dedifferentiation, an effect inhibited by wortmannin. In conclusion, insulin's ability to maintain VSMC quiescence and reverse the dedifferentiating influence of PDGF is mediated via the PI3K pathway, whereas insulin promotes VSMC migration via the MAPK pathway. Thus, with impaired PI 3-kinase signaling and intact MAPK signaling, as seen in insulin resistance, insulin may lose its ability to maintain VSMC quiescence and instead promote VSMC migration.
D000730:Androstadienes / Q000008:administration & dosage; D000818:Animals; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007328:Insulin; D010982:Platelet-Derived Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin