title: The role of vascular-derived perlecan in modulating cell adhesion, proliferation and growth factor signaling.
abstract: Smooth muscle cell proliferation can be inhibited by heparan sulfate proteoglycans whereas the removal or digestion of heparan sulfate from perlecan promotes their proliferation. In this study we characterized the glycosaminoglycan side chains of perlecan isolated from either primary human coronary artery smooth muscle or endothelial cells and determined their roles in mediating cell adhesion and proliferation, and in fibroblast growth factor (FGF) binding and signaling. Smooth muscle cell perlecan was decorated with both heparan sulfate and chondroitin sulfate, whereas endothelial perlecan contained exclusively heparan sulfate chains. Smooth muscle cells bound to the protein core of perlecan only when the glycosaminoglycans were removed, and this binding involved a novel site in domain III as well as domain V/endorepellin and the α2β1 integrin. In contrast, endothelial cells adhered to the protein core of perlecan in the presence of glycosaminoglycans. Smooth muscle cell perlecan bound both FGF1 and FGF2 via its heparan sulfate chains and promoted the signaling of FGF2 but not FGF1. Also endothelial cell perlecan bound both FGF1 and FGF2 via its heparan sulfate chains, but in contrast, promoted the signaling of both growth factors. Based on this differential bioactivity, we propose that perlecan synthesized by smooth muscle cells differs from that synthesized by endothelial cells by possessing different signaling capabilities, primarily, but not exclusively, due to a differential glycanation. The end result is a differential modulation of cell adhesion, proliferation and growth factor signaling in these two key cellular constituents of blood vessels.
authors: Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: m.lord@unsw.edu.au.
authors: Megan S
authors: MS
authors: Lord
authors: Heart Research Institute, Newtown, Sydney, NSW 2042 Australia; Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia.
authors: Christine Y
authors: CY
authors: Chuang
authors: Raymond Purves Research Laboratories, Institute of Bone and Joint Research, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors: James
authors: J
authors: Melrose
authors: Heart Research Institute, Newtown, Sydney, NSW 2042 Australia; Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia.
authors: Michael J
authors: MJ
authors: Davies
authors: Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Renato V
authors: RV
authors: Iozzo
authors: Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia.
authors: John M
authors: JM
authors: Whitelock
mesh_terms: D000704:Analysis of Variance; D002448:Cell Adhesion / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D002809:Chondroitin Sulfates / Q000378:metabolism; D002853:Chromatography, Liquid; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D053719:Tandem Mass Spectrometry
chemical_list: D002809:Chondroitin Sulfates; D017931:DNA Primers; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D036341:Intercellular Signaling Peptides and Proteins; C071927:perlecan
keywords: Endothelial cell; Extracellular matrix; Fibroblast growth factors; Glycosaminoglycan; Perlecan; Smooth muscle cell