title: Activation of vascular smooth muscle cells by TNF and PDGF: overlapping and complementary signal transduction mechanisms.
abstract: OBJECTIVE
  Because tumor necrosis factor-alpha (TNF) has been implicated in the pathogenesis of vein graft neointimal hyperplasia, we sought to determine mechanisms by which TNF could induce proliferative and migratory responses in smooth muscle cells (SMCs).
  
  
  RESULTS
  In rabbit jugulocarotid interposition vein grafts, SMCs expressed TNF as early as four days postoperatively. In rabbit aortic SMCs, TNF and platelet-derived growth factor (PDGF) elicited comparable migration (1.7-fold/basal), and their effects were partially additive. In contrast, while TNF failed to promote SMC [(3)H]thymidine incorporation alone, it doubled the [(3)H]thymidine incorporation observed with PDGF alone. To gain mechanistic insight into these phenomena, we found that TNF and PDGF each activated p38(mapk) equivalently in SMCs, but that PDGF was two to three times more efficacious than TNF in activating SMC extracellular signal-regulated kinases (ERK) 1 and 2 and phosphoinositide 3-kinase. However, only TNF activated NF kappa B. SMC [(3)H]thymidine incorporation that depended on TNF, but not PDGF, was abolished by overexpression of a dominant-negative I kappa B alpha mutant. Inhibition of ERK activation by U0126 reduced SMC migration stimulated only by PDGF (by 35%, P<0.05), but not by TNF. Inhibition of phosphoinositide 3-kinase by LY294002, however, significantly reduced both TNF- and PDGF-stimulated chemotaxis (by 38-54%, P<0.05). In contrast, both U0126 and LY294002 abolished SMC [(3)H]thymidine incorporation induced by either TNF, PDGF, or both agonists.
  
  
  CONCLUSIONS
  In primary rabbit SMCs, TNF promotes migration and mitogenesis through signaling mechanisms that are both distinct from and overlapping with those employed by PDGF. TNF-induced SMC mitogenesis requires complementary co-stimulation with other growth factors.
authors.affiliation: Department of Medicine (Cardiology), Duke University Medical Center, Box 3187, Durham, NC 27710, USA. karsten.peppel@duke.edu
authors.forename: Karsten
authors.initials: K
authors.lastname: Peppel
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhang
authors.forename: Eric S
authors.initials: ES
authors.lastname: Orman
authors.forename: Per-Otto
authors.initials: PO
authors.lastname: Hagen
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
authors.forename: Leigh
authors.initials: L
authors.lastname: Brian
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Freedman
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D006083:Graft Occlusion, Vascular / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology*; D017539:Tunica Intima / Q000473:pathology; D014680:Veins / Q000637:transplantation
chemical_list: D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; D014409:Tumor Necrosis Factor-alpha