C-reactive protein and vein graft disease: evidence for a direct effect on smooth muscle cell phenotype via modulation of PDGF receptor-beta.
Plasma C-reactive protein (CRP) concentration is a biomarker of systemic atherosclerosis and may also be associated with vein graft disease. It remains unclear whether CRP is also an important modulator of biological events in the vessel wall. We hypothesized that CRP influences vein graft healing by stimulating smooth muscle cells (SMCs) to undergo a phenotypic switch. Distribution of CRP was examined by immunohistochemistry in prebypass human saphenous veins (HSVs, n = 21) and failing vein grafts (n = 18, 25-4,400 days postoperatively). Quiescent HSV SMCs were stimulated with human CRP (5-50 microg/ml). SMC migration was assessed in modified Boyden chambers with platelet-derived growth factor (PDGF)-BB (5-10 ng/ml) as the chemoattractant. SMC viability and proliferation were assessed by trypan blue exclusion and reduction of Alamar Blue substrate, respectively. Expression of PDGF ligand and receptor (PDGFR) genes was examined at RNA and protein levels after 24-72 h of CRP exposure. CRP staining was present in 13 of 18 diseased vein grafts, where it localized to the deep media and adventitia, but it was minimally detectable in most prebypass veins. SMCs pretreated with CRP demonstrated a dose-dependent increase in migration to PDGF-BB (P = 0.02), which was inhibited by a PDGF-neutralizing antibody. SMCs treated with CRP showed a dose-dependent increase in PDGFRbeta expression and phosphorylation after 24-48 h. Exogenous CRP had no effect on SMC viability or proliferation. These data suggest that CRP is detectable within the wall of most diseased vein grafts, where it may exert local effects. Clinically relevant levels of CRP can stimulate SMC migration by a mechanism that may involve upregulation and activation of PDGFRbeta.
Ho
Karen J
KJ
Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Owens
Christopher D
CD
Longo
Thomas
T
Sui
Xin X
XX
Ifantides
Cristos
C
Conte
Michael S
MS
D001808:Blood Vessels / Q000637:transplantation*; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004549:Elastin / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000503:physiopathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D032389:Myocytes, Smooth Muscle / Q000473:pathology* / Q000648:ultrastructure*; D010641:Phenotype; D010766:Phosphorylation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology*; D014182:Transplantation, Autologous
D002097:C-Reactive Protein; D004549:Elastin; D020797:Receptor, Platelet-Derived Growth Factor beta