Integrin-linked kinase in the vascular smooth muscle cell response to injury.
Integrin-mediated interactions between smooth muscle cells (SMCs) and the extracellular matrix regulate cell migration and proliferation during neointimal hyperplasia. Integrin-linked kinase (ILK) is a serine-threonine kinase and scaffolding molecule that acts downstream of integrin receptors to modulate cell adhesion; therefore, we examined ILK function in SMCs during wound repair. Silencing of ILK expression with siRNA in vitro decreased cell adhesion to fibronectin and accelerated both cell proliferation and wound closure in the cell monolayer; it also resulted in the rearrangement of focal adhesions and diminished central actin stress fibers. Akt and GSK3beta are ILK substrates that are important in cell motility; however, ILK siRNA silencing did not attenuate injury-induced increases in Akt and GSK3beta phosphorylation. Following balloon catheter injury of the rat carotid artery in vivo, a dramatic decrease in ILK levels coincided with both the proliferation and migration of SMCs, which leads to the formation of a thickened neointima. Immunostaining revealed decreased ILK levels in the media and deep layers of the neointima, but increased ILK levels in the subluminal layers of the intima. Taken together, these results suggest that ILK functions to maintain SMC quiescence in the normal artery. A decrease in ILK levels after injury may permit SMC migration, proliferation, and neointimal thickening, and its re-expression at the luminal surface may attenuate this process during later stages of the injury response.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Bernard
B
Ho
Guangpei
G
Hou
J Geoffrey
JG
Pickering
Gregory
G
Hannigan
B Lowell
BL
Langille
Michelle P
MP
Bendeck
D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D020212:Carotid Artery Injuries / Q000201:enzymology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000201:enzymology / Q000293:injuries; D014945:Wound Healing / Q000502:physiology*; D000099200:Scaffold Protein ILK
D000199:Actins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D051419:Paxillin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D000099200:Scaffold Protein ILK; C000605508:Gsk3b protein, rat