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Diabetes 52:2562-2569, 2003
© 2003 by the American Diabetes Association, Inc.

Insulin Affects Vascular Smooth Muscle Cell Phenotype and Migration Via Distinct Signaling Pathways

Cecilia C. Low Wang1,2, Inga Gurevich1, and Boris Draznin1,2

1 Veterans Affairs Research Service, Denver VA Medical Center, Denver, Colorado
2 Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

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.

Address correspondencereprint requests to Dr. Boris Draznin, ACOS, Research Service, 1055 Clermont Street (151), Denver, CO 80220. E-mail: Boris.Draznin{at}med.va.gov


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