Antagonism of stem cell factor/c-kit signaling attenuates neonatal chronic hypoxia-induced pulmonary vascular remodeling

Karen Young, Eneida Torres, Dorothy Hehre, Shu Wu, Cleide Suguihara, Joshua Hare

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background:Accumulating evidence suggests that c-kit-positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/c-kit-regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis.Methods:Neonatal FVB/NJ mice treated with nonimmune IgG (placebo), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1-Kit W-v/+) and their congenic controls, were exposed to normoxia (FiO 2 = 0.21) or hypoxia (FiO 2 = 0.12) for 2 wk. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation, and remodeling were evaluated.Results:As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling, and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation, and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation.Conclusion:SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH.

Original languageEnglish (US)
Pages (from-to)637-646
Number of pages10
JournalPediatric Research
Volume79
Issue number4
DOIs
StatePublished - Apr 1 2016

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Stem Cell Factor
Lung
Right Ventricular Hypertrophy
Pulmonary Hypertension
Ventricular Pressure
Blood Vessels
Blood Pressure
Cell Proliferation
Extracellular Signal-Regulated MAP Kinases
Vascular Remodeling
Hypoxia
Neutralizing Antibodies
Protein Kinases
Immunoglobulin G
Placebos

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Antagonism of stem cell factor/c-kit signaling attenuates neonatal chronic hypoxia-induced pulmonary vascular remodeling. / Young, Karen; Torres, Eneida; Hehre, Dorothy; Wu, Shu; Suguihara, Cleide; Hare, Joshua.

In: Pediatric Research, Vol. 79, No. 4, 01.04.2016, p. 637-646.

Research output: Contribution to journalArticle

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abstract = "Background:Accumulating evidence suggests that c-kit-positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/c-kit-regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis.Methods:Neonatal FVB/NJ mice treated with nonimmune IgG (placebo), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1-Kit W-v/+) and their congenic controls, were exposed to normoxia (FiO 2 = 0.21) or hypoxia (FiO 2 = 0.12) for 2 wk. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation, and remodeling were evaluated.Results:As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling, and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation, and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation.Conclusion:SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH.",
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AU - Torres, Eneida

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AU - Wu, Shu

AU - Suguihara, Cleide

AU - Hare, Joshua

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N2 - Background:Accumulating evidence suggests that c-kit-positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/c-kit-regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis.Methods:Neonatal FVB/NJ mice treated with nonimmune IgG (placebo), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1-Kit W-v/+) and their congenic controls, were exposed to normoxia (FiO 2 = 0.21) or hypoxia (FiO 2 = 0.12) for 2 wk. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation, and remodeling were evaluated.Results:As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling, and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation, and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation.Conclusion:SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH.

AB - Background:Accumulating evidence suggests that c-kit-positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/c-kit-regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis.Methods:Neonatal FVB/NJ mice treated with nonimmune IgG (placebo), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1-Kit W-v/+) and their congenic controls, were exposed to normoxia (FiO 2 = 0.21) or hypoxia (FiO 2 = 0.12) for 2 wk. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation, and remodeling were evaluated.Results:As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling, and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation, and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation.Conclusion:SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH.

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