title: Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury.
abstract: Perlecan is a proteoglycan composed of a 470-kDa core protein linked to three heparan sulfate (HS) glycosaminoglycan chains. The intact proteoglycan inhibits the smooth muscle cell (SMC) response to vascular injury. Hspg2(Δ3/Δ3) (MΔ3/Δ3) mice produce a mutant perlecan lacking the HS side chains. The objective of this study was to determine differences between these two types of perlecan in modifying SMC activities to the arterial injury response, in order to define the specific role of the HS side chains. In vitro proliferative and migratory activities were compared in SMC isolated from MΔ3/Δ3 and wild-type mice. Proliferation of MΔ3/Δ3 SMC was 1.5× greater than in wild type (P < 0.001), increased by addition of growth factors, and showed a 42% greater migratory response than wild-type cells to PDGF-BB (P < 0.001). In MΔ3/Δ3 SMC adhesion to fibronectin, and collagen types I and IV was significantly greater than wild type. Addition of DRL-12582, an inducer of perlecan expression, decreased proliferation and migratory response to PDGF-BB stimulation in wild-type SMC compared with MΔ3/Δ3. In an in vivo carotid artery wire injury model, the medial thickness, medial area/lumen ratio, and macrophage infiltration were significantly increased in the MΔ3/Δ3 mice, indicating a prominent role of the HS side chain in limiting vascular injury response. Mutant perlecan that lacks HS side chains had a marked reduction in the inhibition of in vitro SMC function and the in vivo arterial response to injury, indicating the critical role of HS side chains in perlecan function in the vessel wall.
authors.affiliation: Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada;
authors.forename: Lara
authors.initials: L
authors.lastname: Gotha
authors.affiliation: Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Korea University Ansan Hospital, Ansan, Korea.
authors.forename: Sang Yup
authors.initials: SY
authors.lastname: Lim
authors.affiliation: Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada;
authors.forename: Azriel B
authors.initials: AB
authors.lastname: Osherov
authors.affiliation: Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada;
authors.forename: Rafael
authors.initials: R
authors.lastname: Wolff
authors.affiliation: Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada;
authors.forename: Beiping
authors.initials: B
authors.lastname: Qiang
authors.affiliation: Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada;
authors.forename: Ilana
authors.initials: I
authors.lastname: Erlich
authors.affiliation: Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada;
authors.forename: Nafiseh
authors.initials: N
authors.lastname: Nili
authors.affiliation: Dr. Reddy's Laboratories, Norcross, Georgia;
authors.forename: Sivaram
authors.initials: S
authors.lastname: Pillarisetti
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; and.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Department of Pediatric Cardiac Surgery, Skane University Hospital, Lund, Sweden;
authors.forename: Phan-Kiet
authors.initials: PK
authors.lastname: Tran
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; and.
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; and.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; and.
authors.forename: Karin
authors.initials: K
authors.lastname: Tran-Lundmark
authors.affiliation: Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Advani
authors.affiliation: Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
authors.affiliation: Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; bradley.strauss@sunnybrook.ca.
authors.forename: Bradley H
authors.initials: BH
authors.lastname: Strauss
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005838:Genotype; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors; D066253:Vascular Remodeling / Q000187:drug effects; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D019812:Heparan Sulfate Proteoglycans; D020574:Proto-Oncogene Proteins c-sis; D016222:Fibroblast Growth Factor 2; C071927:perlecan; D000077214:Becaplermin
keywords: arterial injury; heparan sulfate proteoglycans; perlecan; smooth muscle cells