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 language | English (US) |
|---|---|
| Pages (from-to) | 637-646 |
| Number of pages | 10 |
| Journal | Pediatric Research |
| Volume | 79 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2016 |
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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 journal › Article
}
TY - JOUR
T1 - Antagonism of stem cell factor/c-kit signaling attenuates neonatal chronic hypoxia-induced pulmonary vascular remodeling
AU - Young, Karen
AU - Torres, Eneida
AU - Hehre, Dorothy
AU - Wu, Shu
AU - Suguihara, Cleide
AU - Hare, Joshua
PY - 2016/4/1
Y1 - 2016/4/1
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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U2 - 10.1038/pr.2015.275
DO - 10.1038/pr.2015.275
M3 - Article
VL - 79
SP - 637
EP - 646
JO - Pediatric Research
JF - Pediatric Research
SN - 0031-3998
IS - 4
ER -