PDGF-dependent β-catenin activation is associated with abnormal pulmonary artery smooth muscle cell proliferation in pulmonary arterial hypertension

FEBS Lett. 2016 Jan;590(1):101-9. doi: 10.1002/1873-3468.12038. Epub 2016 Jan 8.

Abstract

Pulmonary arterial hypertension (PAH) is characterized by excessive pulmonary arterial smooth muscle cells (PASMCs) growth, partially in response to PDGF-BB but whether this is dependent on β-catenin (βC) activation is unclear. Compared to healthy cells, PAH PASMCs demonstrate higher levels of proliferation both at baseline and with PDGF-BB that correlate with GSK3β dependent βC activation. We show that βC knockdown but not Wnt5a stimulation reduces PDGF-BB dependent growth and normalizes PAH PASMCs proliferation. These findings support that cross-talk between PDGF and Wnt signaling modulates PASMC proliferation and suggest that βC targeted therapies could treat abnormal vascular remodeling in PAH.

Keywords: PDGF; Wnt signaling; pulmonary disease; pulmonary hypertension; smooth muscle cells; vascular remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Anticoagulants / pharmacology
  • Becaplermin
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Familial Primary Pulmonary Hypertension / metabolism*
  • Familial Primary Pulmonary Hypertension / pathology
  • Gene Expression Regulation / drug effects
  • Genes, Reporter / drug effects
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-sis / chemistry
  • Proto-Oncogene Proteins c-sis / metabolism*
  • Proto-Oncogene Proteins c-sis / pharmacology
  • Pulmonary Artery / cytology
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / pathology
  • RNA Interference
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Wnt Proteins / antagonists & inhibitors
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway* / drug effects
  • Wnt-5a Protein
  • beta Catenin / agonists*
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Anticoagulants
  • CTNNB1 protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-sis
  • Recombinant Proteins
  • WNT5A protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • beta Catenin
  • Becaplermin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3