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.
© 2015 Federation of European Biochemical Societies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Anticoagulants / pharmacology
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Becaplermin
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Cell Proliferation / drug effects
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Cells, Cultured
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Familial Primary Pulmonary Hypertension / metabolism*
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Familial Primary Pulmonary Hypertension / pathology
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Gene Expression Regulation / drug effects
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Genes, Reporter / drug effects
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Glycogen Synthase Kinase 3 / metabolism*
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Glycogen Synthase Kinase 3 beta
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Humans
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism*
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Muscle, Smooth, Vascular / pathology
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Phosphorylation / drug effects
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Promoter Regions, Genetic / drug effects
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Protein Processing, Post-Translational / drug effects
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-sis / chemistry
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Proto-Oncogene Proteins c-sis / metabolism*
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Proto-Oncogene Proteins c-sis / pharmacology
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Pulmonary Artery / cytology
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Pulmonary Artery / drug effects
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Pulmonary Artery / metabolism*
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Pulmonary Artery / pathology
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RNA Interference
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Wnt Proteins / antagonists & inhibitors
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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Wnt Signaling Pathway* / drug effects
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Wnt-5a Protein
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beta Catenin / agonists*
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beta Catenin / antagonists & inhibitors
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Anticoagulants
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CTNNB1 protein, human
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-sis
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Recombinant Proteins
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WNT5A protein, human
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Wnt Proteins
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Wnt-5a Protein
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beta Catenin
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Becaplermin
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3