Enhanced proliferation and migration of vascular smooth muscle cells in response to vascular injury under hyperglycemic conditions is controlled by beta3 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, beta3 integrin inhibition in diabetic patients confers protection from restenosis, little is known regarding the role of beta3 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 beta3 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 PKCbeta in an integrin beta3-dependent manner. Hyperglycemia also promoted SMC filopodia formation and cell migration, both of which required alphaVbeta3, PKCbeta, and ERK activity. Furthermore, the integrin-kinase association was regulated by the alphaVbeta3 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 beta3 integrin signaling.
Panchatcharam
Manikandan
M
Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY 40536-0200, United States. manikandan@uky.edu
Miriyala
Sumitra
S
Yang
Fanmuyi
F
Leitges
Michael
M
Chrzanowska-Wodnicka
Magdalena
M
Quilliam
Lawrence A
LA
Anaya
Paul
P
Morris
Andrew J
AJ
Smyth
Susan S
SS
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003925:Diabetic Angiopathies; D004730:Endothelium, Vascular / Q000293:injuries / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D015398:Signal Transduction / Q000187:drug effects; D019699:Thrombospondins / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
D039302:Integrin alphaVbeta3; D019699:Thrombospondins; D011493:Protein Kinase C; D064546:Protein Kinase C beta