Smooth muscle cell matrix metalloproteinase production is stimulated via alpha(v)beta(3) integrin.
This study tests the hypothesis that alpha(v)beta(3) integrin receptors play a critical role in smooth muscle cell (SMC) migration after arterial injury and facilitate migration through the upregulation of matrix metalloproteinase (MMP) activity. We showed that beta(3) integrin mRNA was upregulated by SMCs in the balloon-injured rat carotid artery in coincidence with MMP-1 expression and early SMC migration. Treatment with the beta(3) integrin-blocking antibody F11 significantly decreased SMC migration into the intima at 4 days after injury, from 110.8+/-30.8 cells/mm(2) in control rats to 10.29+/-7.03 cells/mm(2) in F11-treated rats (P=0.008). By contrast, there was no effect on medial SMC proliferation or on medial SMC number in the carotid artery at 4 days. In vitro, we found that human newborn SMCs produced MMP-1 but that adult SMCs did not. This was possibly due to the fact that newborn SMCs expressed alpha(v)beta(3) integrin receptors, whereas adult SMCs did not. Stimulation of newborn (alpha(v)beta(3)+) SMCs with osteopontin, a matrix ligand for alpha(v)beta(3), increased MMP-1 production from 114.4+/-35.8 ng/mL at 0 nmol/L osteopontin to 232.5+/-57.5 ng/mL at 100 nmol/L osteopontin. Finally, we showed that stimulation of newborn SMCs with platelet-derived growth factor-BB and osteopontin together increased the SMC production of MMP-9. Thus, our results support the hypothesis that SMC alpha(v)beta(3) integrin receptors play an important role in regulating migration by stimulating SMC MMP production.
Bendeck
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Terrence Donnelly Research Laboratories, Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. bendeckm@smh.toronto.on.ca
Irvin
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Reidy
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Smith
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Mulholland
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Horton
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Giachelli
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D000818:Animals; D000077214:Becaplermin; D001792:Blood Platelets / Q000502:physiology; D020212:Carotid Artery Injuries / Q000378:metabolism; D002404:Catheterization; D002465:Cell Movement; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D053495:Osteopontin; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019030:Receptors, Vitronectin / Q000235:genetics / Q000502:physiology*; D012795:Sialoglycoproteins / Q000494:pharmacology
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D019030:Receptors, Vitronectin; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C506897:Spp1 protein, rat; D053495:Osteopontin; D000077214:Becaplermin; D020781:Matrix Metalloproteinase 1