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Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGFβ receptor-JNK1 signalling

Evgeniy Panzhinskiy1, W Michael Zawada, Kurt R Stenmark

  • 1Department of Pharmaceutical Sciences, University of Wyoming, Laramie, WY, USA.

Cardiovascular Research
|June 28, 2012
PubMed

Insights

Hypoxia-induced pulmonary hypertension (PH) involves increased pulmonary artery fibroblast proliferation. The platelet-derived growth factor β receptor (PDGFβ-R) and c-Jun N-terminal kinase 1 (JNK1) pathway drives this proliferation, offering a potential therapeutic target for PH.

Area of Science:

  • Cardiovascular Research
  • Cell Biology
  • Pulmonary Medicine

Background:

  • Pulmonary hypertension (PH) is a proliferative vascular disease with no current disease-modifying therapies.
  • Adventitial fibroblasts in the pulmonary artery (PA) wall show increased replication in hypoxia-induced PH models.
  • Elevated platelet-derived growth factor β receptor (PDGFβ-R) signaling is implicated in PH pathogenesis.

Purpose of the Study:

  • To investigate the role of PDGFβ-R activation in fibroblast proliferation and adventitial remodeling in PH.
  • To test the hypothesis that PDGFβ-R signaling contributes to the cellular changes observed in PH.

Main Methods:

  • Newborn calves were exposed to high altitude to induce PH.
  • Measured PDGFβ-R phosphorylation in PA adventitia and cultured fibroblasts.
  • Utilized PDGF-BB stimulation and pharmacological/siRNA inhibition of JNK1 to assess proliferation.

Main Results:

  • Hypoxia-induced PH calves exhibited elevated PDGFβ-R phosphorylation in PA adventitia and fibroblasts.
  • PDGF-BB stimulation increased proliferation in PH fibroblasts, dependent on reactive oxygen species and ERK1/2.
  • PDGFβ-R-mediated proliferation in PH cells uniquely required c-Jun N-terminal kinase 1 (JNK1) activation.

Conclusions:

  • Hypoxia-induced changes in pulmonary artery cells involve the PDGFβ-R-JNK1 axis.
  • This axis confers heightened fibroblast proliferation and adventitial remodeling in PH.
  • Targeting the PDGFβ-R-JNK1 pathway may offer a novel therapeutic strategy for PH.
Abstract

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