Enhanced proliferation and migration of vascular smooth muscle cells in response to vascular injury under hyperglycemic conditions is controlled by β3 integrin signaling

Atheroma formation and restenosis following percutaneous vascular intervention involve the growth and migration of vascular smooth muscle cells (SMCs) into neointimal lesions, in part due to changes in the extracellular matrix. While some clinical studies have suggested that, in comparison to non-diabetics, beta 3 integrin inhibition in diabetic patients confers protection from restenosis, little is known regarding the role of beta 3 integrin inhibition on SMC responses in this context To understand the molecular mechanisms underlying integrin-mediated regulation of SMC function in diabetes, we examined SMC responses in diabetic mice deficient in integrin beta 3 and observed that the integrin was required for enhanced proliferation, migration and extracellular regulated kinase (ERK) activation Hyperglycemia-enhanced membrane recruitment and catalytic activity of PKC beta in an integrin beta 3-dependent manner Hyperglycemia also promoted SMC filopodia formation and cell migration, both of which required alpha V beta 3, PKC beta, and ERK activity Furthermore, the integrin-kinase association was regulated by the alpha V beta 3 integrin ligand thrombospondin and the integrin modulator Rap1 under conditions of hyperglycemia These results suggest that there are differences in SMC responses to vascular injury depending on the presence or absence of hyperglycemia and that SMC response under hyperglycemic conditions is largely mediated through beta 3 integrin signaling Published by Elsevier Ltd.