title: Antagonism of stem cell factor/c-kit signaling attenuates neonatal chronic hypoxia-induced pulmonary vascular remodeling.
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 (FiO2 = 0.21) or hypoxia (FiO2 = 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.|Batchelor Children's Research Institute, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.|The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Young
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.|Batchelor Children's Research Institute, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Eneida
authors.initials: E
authors.lastname: Torres
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.|Batchelor Children's Research Institute, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hehre
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.|Batchelor Children's Research Institute, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Shu
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.|Batchelor Children's Research Institute, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Cleide
authors.initials: C
authors.lastname: Suguihara
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.|Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Joshua M
authors.identifier: http://orcid.org/0000-0002-7751-5032
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply*; D020935:MAP Kinase Signaling System; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000276:immunology / Q000378:metabolism*; D066253:Vascular Remodeling
chemical_list: D057134:Antibodies, Neutralizing; D019089:Stem Cell Factor