Inhibition of PDGF-stimulated and matrix-mediated proliferation of human vascular smooth muscle cells by SPARC is independent of changes in cell shape or cyclin-dependent kinase inhibitors.
Interactions among growth factors, cells, and extracellular matrix regulate proliferation during normal development and in pathologies such as atherosclerosis. SPARC (secreted protein, acidic, and rich in cysteine) is a matrix-associated glycoprotein that modulates the adhesion and proliferation of vascular cells. In this study, we demonstrate that SPARC inhibits human arterial smooth muscle cell proliferation stimulated by platelet-derived growth factor or by adhesion to monomeric type I collagen. Binding studies with SPARC and SPARC peptides indicate specific and saturable interaction with smooth muscle cells that involves the C-terminal Ca2+-binding region of the protein. We also report that SPARC arrests monomeric collagen-supported smooth muscle cell proliferation in the late G1-phase of the cell cycle in the absence of an effect on cell shape or on levels of cyclin-dependent kinase inhibitors. Cyclin-dependent kinase-2 activity, p107 and cyclin A levels, and retinoblastoma protein phosphorylation are markedly reduced in response to the addition of exogenous SPARC and/or peptides derived from specific domains of SPARC. Thus, SPARC, previously characterized as an inhibitor of platelet-derived growth factor binding to its receptor, also antagonizes smooth muscle cell proliferation mediated by monomeric collagen at the level of cyclin-dependent kinase-2 activity.
Motamed
Kouros
K
Department of Vascular Biology, The Hope Heart Institute, Seattle, Washington 98104, USA.
Funk
Sarah E
SE
Koyama
Hidenori
H
Ross
Russell
R
Raines
Elaine W
EW
Sage
E Helene
EH
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D015676:Osteonectin / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism
D024042:Collagen Type I; D004791:Enzyme Inhibitors; D015676:Osteonectin; D010455:Peptides; D010982:Platelet-Derived Growth Factor; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases