Type VIII collagen stimulates smooth muscle cell migration and matrix metalloproteinase synthesis after arterial injury.
Type VIII collagen is a matrix protein expressed in a number of tissues undergoing active remodeling, including injured arteries during neointimal formation and in human atherosclerotic plaques; however, very little is known about its function. We have investigated whether the type VIII collagen stimulates smooth muscle cell (SMC) migration and invasion by binding to integrin receptors and up-regulating matrix metalloproteinase (MMP) production. SMCs attached to plates coated with type VIII collagen in a dose-dependent manner, with maximal attachment occurring with coating solutions containing 25 microgram/ml collagen. Type VIII collagen at 100 microgram/ml stimulated an 83-fold increase in the migration of SMCs in a chemotaxis chamber. Antibodies against beta1 integrin receptors prevented attachment and migration of SMCs. Antibodies against alpha1 or alpha2 integrins reduced attachment of SMCs to type VIII collagen by 29% and 77%, respectively. We found that SMCs grown from the rat neointima, but not medial SMCs, increased their production of MMP-2 and -9 on adherence to type VIII collagen. This suggests that there is an important difference in phenotype between intimal and medial SMCs and that intimal SMCs have distinct matrix-dependent signaling mechanisms. Our findings suggest that type VIII collagen deposited in vascular lesions functions to promote SMC attachment and chemotaxis, and signals through integrin receptors to stimulate MMP synthesis, all of which are important mechanisms used in cell migration and invasion.
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Terrence Donnelly Research Laboratories, Division of Cardiology, St. Michael's Hospital, Department of Medicine, Toronto, Ontario, Canada.
Mulholland
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Gronska
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Bendeck
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MP
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000201:enzymology / Q000293:injuries* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology / Q000502:physiology*; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D039222:Integrin alpha1beta1; D016023:Integrins / Q000502:physiology; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D038981:Receptors, Collagen; D017539:Tunica Intima / Q000201:enzymology; D017540:Tunica Media / Q000201:enzymology; D014947:Wounds and Injuries / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*
D039222:Integrin alpha1beta1; D016023:Integrins; D038981:Receptors, Collagen; D003094:Collagen; D018093:Gelatinases; D020782:Matrix Metalloproteinases