Fibroblast growth factor receptor-1 signaling induces osteopontin expression and vascular smooth muscle cell-dependent adventitial fibroblast migration in vitro

Guohong Li, Suzanne Oparil, Stacey S. Kelpke, Yiu Fai Chen, John A. Thompson

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Background - Increased expression of osteopontin (OPN), fibroblast growth factors (FGFs), and their type-1 receptor (FGFR-1) is associated with neointima formation and atherosclerosis. This study tested the hypothesis that ligand activation of FGFR-1 stimulates OPN expression in rat aortic smooth muscle cells (RASMCs), explored the signaling pathway involved, and assessed the functional consequences of activating this pathway on adventitial fibroblast (AF) migration in vitro. Methods and Results - Exogenous FGF-1 stimulated expression of OPN mRNA and protein in RASMCs in vitro in a dose and time-dependent manner. OPN mRNA induction by FGF-1 was completely inhibited by either actinomycin D or cycloheximide, selective inhibitors of RNA polymerase and protein synthesis, respectively. OPN mRNA induction by FGF-1 was attenuated by PD 166866, a highly selective and potent FGFR-1 tyrosine kinase inhibitor. Addition of either PP2 or PD98059, specific inhibitors of Src and mitogen-activated extracellular signal-regulated kinase (MEK)/mitogenactivated protein (MAP) kinases, respectively, attenuated FGF-1-stimulated OPN mRNA expression. FGF-1 treatment of RASMCs enhanced RASMC-conditioned medium-stimulated AF migration; this effect was inhibited by pretreatment of RASMCs with either PD166866 or PP2. Immunodepletion of OPN from RASMC-conditioned medium inhibited both basal and FGF-1-stimulated AF migration. Conclusions - This in vitro study provided a first indication that ligand-activated FGFR-1 plays a significant role in upregulation of OPN expression at the transcriptional level via signaling to Src/MEK/MAP kinases in RASMCs and that this pathway is functionally significant in mediating AF migration via stimulation of OPN expression.

Original languageEnglish (US)
Pages (from-to)854-859
Number of pages6
JournalCirculation
Volume106
Issue number7
DOIs
StatePublished - Aug 13 2002

Fingerprint

Receptor, Fibroblast Growth Factor, Type 1
Adventitia
Osteopontin
Vascular Smooth Muscle
Smooth Muscle Myocytes
Fibroblast Growth Factor 1
Fibroblasts
Messenger RNA
Mitogen-Activated Protein Kinase Kinases
Conditioned Culture Medium
Protein Kinases
Ligands
Nucleic Acid Synthesis Inhibitors
In Vitro Techniques
Neointima
Protein Synthesis Inhibitors
Extracellular Signal-Regulated MAP Kinases
Dactinomycin
DNA-Directed RNA Polymerases
Cycloheximide

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

@article{0ea512bef7a64b28a2007a831266bbfd,
title = "Fibroblast growth factor receptor-1 signaling induces osteopontin expression and vascular smooth muscle cell-dependent adventitial fibroblast migration in vitro",
abstract = "Background - Increased expression of osteopontin (OPN), fibroblast growth factors (FGFs), and their type-1 receptor (FGFR-1) is associated with neointima formation and atherosclerosis. This study tested the hypothesis that ligand activation of FGFR-1 stimulates OPN expression in rat aortic smooth muscle cells (RASMCs), explored the signaling pathway involved, and assessed the functional consequences of activating this pathway on adventitial fibroblast (AF) migration in vitro. Methods and Results - Exogenous FGF-1 stimulated expression of OPN mRNA and protein in RASMCs in vitro in a dose and time-dependent manner. OPN mRNA induction by FGF-1 was completely inhibited by either actinomycin D or cycloheximide, selective inhibitors of RNA polymerase and protein synthesis, respectively. OPN mRNA induction by FGF-1 was attenuated by PD 166866, a highly selective and potent FGFR-1 tyrosine kinase inhibitor. Addition of either PP2 or PD98059, specific inhibitors of Src and mitogen-activated extracellular signal-regulated kinase (MEK)/mitogenactivated protein (MAP) kinases, respectively, attenuated FGF-1-stimulated OPN mRNA expression. FGF-1 treatment of RASMCs enhanced RASMC-conditioned medium-stimulated AF migration; this effect was inhibited by pretreatment of RASMCs with either PD166866 or PP2. Immunodepletion of OPN from RASMC-conditioned medium inhibited both basal and FGF-1-stimulated AF migration. Conclusions - This in vitro study provided a first indication that ligand-activated FGFR-1 plays a significant role in upregulation of OPN expression at the transcriptional level via signaling to Src/MEK/MAP kinases in RASMCs and that this pathway is functionally significant in mediating AF migration via stimulation of OPN expression.",
author = "Guohong Li and Suzanne Oparil and Kelpke, {Stacey S.} and Chen, {Yiu Fai} and Thompson, {John A.}",
year = "2002",
month = "8",
day = "13",
doi = "10.1161/01.CIR.0000024113.26985.CC",
language = "English (US)",
volume = "106",
pages = "854--859",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

Fibroblast growth factor receptor-1 signaling induces osteopontin expression and vascular smooth muscle cell-dependent adventitial fibroblast migration in vitro. / Li, Guohong; Oparil, Suzanne; Kelpke, Stacey S.; Chen, Yiu Fai; Thompson, John A.

In: Circulation, Vol. 106, No. 7, 13.08.2002, p. 854-859.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fibroblast growth factor receptor-1 signaling induces osteopontin expression and vascular smooth muscle cell-dependent adventitial fibroblast migration in vitro

AU - Li, Guohong

AU - Oparil, Suzanne

AU - Kelpke, Stacey S.

AU - Chen, Yiu Fai

AU - Thompson, John A.

PY - 2002/8/13

Y1 - 2002/8/13

N2 - Background - Increased expression of osteopontin (OPN), fibroblast growth factors (FGFs), and their type-1 receptor (FGFR-1) is associated with neointima formation and atherosclerosis. This study tested the hypothesis that ligand activation of FGFR-1 stimulates OPN expression in rat aortic smooth muscle cells (RASMCs), explored the signaling pathway involved, and assessed the functional consequences of activating this pathway on adventitial fibroblast (AF) migration in vitro. Methods and Results - Exogenous FGF-1 stimulated expression of OPN mRNA and protein in RASMCs in vitro in a dose and time-dependent manner. OPN mRNA induction by FGF-1 was completely inhibited by either actinomycin D or cycloheximide, selective inhibitors of RNA polymerase and protein synthesis, respectively. OPN mRNA induction by FGF-1 was attenuated by PD 166866, a highly selective and potent FGFR-1 tyrosine kinase inhibitor. Addition of either PP2 or PD98059, specific inhibitors of Src and mitogen-activated extracellular signal-regulated kinase (MEK)/mitogenactivated protein (MAP) kinases, respectively, attenuated FGF-1-stimulated OPN mRNA expression. FGF-1 treatment of RASMCs enhanced RASMC-conditioned medium-stimulated AF migration; this effect was inhibited by pretreatment of RASMCs with either PD166866 or PP2. Immunodepletion of OPN from RASMC-conditioned medium inhibited both basal and FGF-1-stimulated AF migration. Conclusions - This in vitro study provided a first indication that ligand-activated FGFR-1 plays a significant role in upregulation of OPN expression at the transcriptional level via signaling to Src/MEK/MAP kinases in RASMCs and that this pathway is functionally significant in mediating AF migration via stimulation of OPN expression.

AB - Background - Increased expression of osteopontin (OPN), fibroblast growth factors (FGFs), and their type-1 receptor (FGFR-1) is associated with neointima formation and atherosclerosis. This study tested the hypothesis that ligand activation of FGFR-1 stimulates OPN expression in rat aortic smooth muscle cells (RASMCs), explored the signaling pathway involved, and assessed the functional consequences of activating this pathway on adventitial fibroblast (AF) migration in vitro. Methods and Results - Exogenous FGF-1 stimulated expression of OPN mRNA and protein in RASMCs in vitro in a dose and time-dependent manner. OPN mRNA induction by FGF-1 was completely inhibited by either actinomycin D or cycloheximide, selective inhibitors of RNA polymerase and protein synthesis, respectively. OPN mRNA induction by FGF-1 was attenuated by PD 166866, a highly selective and potent FGFR-1 tyrosine kinase inhibitor. Addition of either PP2 or PD98059, specific inhibitors of Src and mitogen-activated extracellular signal-regulated kinase (MEK)/mitogenactivated protein (MAP) kinases, respectively, attenuated FGF-1-stimulated OPN mRNA expression. FGF-1 treatment of RASMCs enhanced RASMC-conditioned medium-stimulated AF migration; this effect was inhibited by pretreatment of RASMCs with either PD166866 or PP2. Immunodepletion of OPN from RASMC-conditioned medium inhibited both basal and FGF-1-stimulated AF migration. Conclusions - This in vitro study provided a first indication that ligand-activated FGFR-1 plays a significant role in upregulation of OPN expression at the transcriptional level via signaling to Src/MEK/MAP kinases in RASMCs and that this pathway is functionally significant in mediating AF migration via stimulation of OPN expression.

UR - http://www.scopus.com/inward/record.url?scp=0037072456&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037072456&partnerID=8YFLogxK

U2 - 10.1161/01.CIR.0000024113.26985.CC

DO - 10.1161/01.CIR.0000024113.26985.CC

M3 - Article

C2 - 12176960

AN - SCOPUS:0037072456

VL - 106

SP - 854

EP - 859

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 7

ER -