Activation of vascular smooth muscle cells by TNF and PDGF: Overlapping and complementary signal transduction mechanisms

Karsten Peppel, Lisheng Zhang, Eric Orman, Per Otto Hagen, Andrea Amalfitano, Leigh Brian, Neil J. Freedman

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Because tumor necrosis factor-α (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). 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 [3H]thymidine incorporation alone, it doubled the [3H]thymidine incorporation observed with PDGF alone. To gain mechanistic insight into these phenomena, we found that TNF and PDGF each activated p38mapk 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 NFκB. SMC [3H]thymidine incorporation that depended on TNF, but not PDGF, was abolished by overexpression of a dominant-negative IκBα 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 [3H]thymidine incorporation induced by either TNF, PDGF, or both agonists. 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.

Original languageEnglish (US)
Pages (from-to)674-682
Number of pages9
JournalCardiovascular Research
Volume65
Issue number3
DOIs
StatePublished - Feb 15 2005
Externally publishedYes

Fingerprint

Platelet-Derived Growth Factor
Vascular Smooth Muscle
Smooth Muscle Myocytes
Signal Transduction
Tumor Necrosis Factor-alpha
Thymidine
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
1-Phosphatidylinositol 4-Kinase
Rabbits
Veins
Transplants
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Extracellular Signal-Regulated MAP Kinases
Chemotaxis
Cell Movement
Hyperplasia
Intercellular Signaling Peptides and Proteins

Keywords

  • Cytokines
  • Growth factors
  • Receptors
  • Signal transduction
  • Veins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Activation of vascular smooth muscle cells by TNF and PDGF : Overlapping and complementary signal transduction mechanisms. / Peppel, Karsten; Zhang, Lisheng; Orman, Eric; Hagen, Per Otto; Amalfitano, Andrea; Brian, Leigh; Freedman, Neil J.

In: Cardiovascular Research, Vol. 65, No. 3, 15.02.2005, p. 674-682.

Research output: Contribution to journalArticle

Peppel, Karsten ; Zhang, Lisheng ; Orman, Eric ; Hagen, Per Otto ; Amalfitano, Andrea ; Brian, Leigh ; Freedman, Neil J. / Activation of vascular smooth muscle cells by TNF and PDGF : Overlapping and complementary signal transduction mechanisms. In: Cardiovascular Research. 2005 ; Vol. 65, No. 3. pp. 674-682.
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abstract = "Because tumor necrosis factor-α (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). 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 [3H]thymidine incorporation alone, it doubled the [3H]thymidine incorporation observed with PDGF alone. To gain mechanistic insight into these phenomena, we found that TNF and PDGF each activated p38mapk 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 NFκB. SMC [3H]thymidine incorporation that depended on TNF, but not PDGF, was abolished by overexpression of a dominant-negative IκBα 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 [3H]thymidine incorporation induced by either TNF, PDGF, or both agonists. 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.",
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AU - Peppel, Karsten

AU - Zhang, Lisheng

AU - Orman, Eric

AU - Hagen, Per Otto

AU - Amalfitano, Andrea

AU - Brian, Leigh

AU - Freedman, Neil J.

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