Decorin inhibition of PDGF-stimulated vascular smooth muscle cell function: potential mechanism for inhibition of intimal hyperplasia after balloon angioplasty.
Decorin is a small proteoglycan that binds to transforming growth factor-beta (TGF-beta) and inhibits its activity. However, its interaction with platelet-derived growth factor (PDGF), involved in arterial repair after injury, is not well characterized. The objectives of this study were to assess decorin-PDGF and decorin-PDGF receptor (PDGFR) interactions, the in vitro effects of decorin on PDGF-stimulated smooth muscle cell (SMC) functions and the in vivo effects of decorin overexpression on arterial repair in a rabbit carotid balloon-injury model. Decorin binding to PDGF was demonstrated by solid-phase binding and affinity cross-linking assays. Decorin potently inhibited PDGF-stimulated PDGFR phosphorylation. Pretreatment of rabbit aortic SMC with decorin significantly inhibited PDGF-stimulated cell migration, proliferation, and collagen synthesis. Decorin overexpression by adenoviral-mediated gene transfection in balloon-injured carotid arteries significantly decreased intimal cross-sectional area and collagen content by approximately 50% at 10 weeks compared to beta-galactosidase-transfected or balloon-injured, non-transfected controls. This study shows that decorin binds to PDGF and inhibits its stimulatory activity on SMCs by preventing PDGFR phosphorylation. Decorin overexpression reduces intimal hyperplasia and collagen content after arterial injury. Decorin may be an effective therapy for the prevention of intimal hyperplasia after balloon angioplasty.
Nili
Nafiseh
N
Roy and Ann Foss Interventional Cardiology Research Program, Terrence Donnelly Heart Centre, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8.
Cheema
Asim N
AN
Giordano
Frank J
FJ
Barolet
Alan W
AW
Babaei
Saeid
S
Hickey
Reed
R
Eskandarian
Mohammad R
MR
Smeets
Mirjam
M
Butany
Jagdish
J
Pasterkamp
Gerard
G
Strauss
Bradley H
BH
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D058575:Decorin; D016326:Extracellular Matrix Proteins; D005353:Fibronectins / Q000378:metabolism; D006965:Hyperplasia / Q000517:prevention & control; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D009336:Necrosis; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D019076:Transgenes; D017539:Tunica Intima / Q000473:pathology
D058575:Decorin; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D003094:Collagen; D004247:DNA; D020797:Receptor, Platelet-Derived Growth Factor beta