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

Abstract

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 nondiabetics, β3 integrin inhibition in diabetic patients confers protection from restenosis, little is known regarding the role of β3 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 β3 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 PKCβ in an integrin β3-dependent manner. Hyperglycemia also promoted SMC filopodia formation and cell migration, both of which required αVβ3, PKCβ, and ERK activity. Furthermore, the integrin-kinase association was regulated by the αVβ3 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 β3 integrin signaling

Breviscapine inhibits high glucose-induced proliferation and migration of cultured vascular smooth muscle cells of rats via suppressing the ERK1/2 MAPK signaling pathway

“…As previously reported [7,10,11,25] , both the PKC inhibitor Ro 31-8220 and the MEK1/2 inhibitor PD 98059 abrogated the high glucoseenhanced proliferation and migration of VSMCs. Thus, the PKC and MAPK pathways were both responsible for mediating the proliferative-and migratory-promoting response of VSMCs in high glucose medium.…”

“…Previous studies have demonstrated that VSMCs that are cultured under hyperglycemic conditions displayed enhanced proliferative and migratory responses compared to cells that are www.chinaphar.com He M et al Acta Pharmacologica Sinica npg cultured under euglycemic conditions, and it has been suggested that protein kinase C (PKC) signal transduction may play an important role in this effect [7,9,10] . Other studies have shown that activation of the mitogen-activated protein kinase (MAPK) pathway may contribute to the increased proliferation and migration of VSMCs in response to hyper glycemia [10,11] .…”

αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation

“…25,26 Our data show that avb3 inhibitors potently inhibit smooth muscle incorporation into early spontaneous atherosclerotic plaques, phenocopying the early reduction in plaque smooth muscle content observed after the deletion of plasma fibronectin. 10 In contrast to avb3, expression of a5b1 is largely limited to plaque endothelial cells and macrophages, and inhibiting a5b1 limits early atherogenesis but does not prevent smooth muscle incorporation into early atherosclerotic plaques.…”

Effect Of Metabolic Syndrome On The Response To Arterial Injury

“…In vitro, diabetes appears to enhance vascular smooth muscle cell proliferation and migration through alterations in proteases, integrins, glycoproteins and formation of Advanced Glycation Endproducts (AGEs) (20,21). In vivo, elevated blood glucose levels have been shown to induce a series of alterations within the vasculature including endothelial dysfunction, cellular proliferation, changes in extracellular matrix conformation and impairment of LDL receptor-mediated uptake decreasing the in vivo clearance of LDL concentrations (22)(23)(24)(25)(26).…”